Institute for Molecular Bioscience Annual Report 2001 · Contribute to world knowledge - human and animal biology, health and medicine Create a platform for excellence in fundamental

Institute for Molecular BioscienceAnnual Report 2001

Institutefor

Molecular

Bioscience

2001A

nnual Report

The IMB Commitment

Contribute to world knowledge - human and animal biology, health and medicine

Create a platform for excellence in fundamental research and postgraduate teaching

Integrate the full spectrum of molecular bioscience from gene discovery to practical applications

Lead by example as an authority in public policy and ethics of new genetics, determining bestoutcomes for worldwide community

Develop Australia’s biotechnology industry and attract international bioindustries to Queensland.

Leadership

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Leadership ............................................................................................ 2

About the IMB .................................................................................................................................... 2

2001 Highlights ................................................................................................................................... 4

Chair’s Report ..................................................................................................................................... 9

Co-directors’ Reports ........................................................................................................................ 10

IMB Board ........................................................................................................................................ 12

Research: From gene discovery to practical applications ............. 18

Genomics and Bioinformatics ........................................................................................................... 18

Cellular and Developmental Biology ................................................................................................ 27

Structural Biology and Chemistry ..................................................................................................... 46

IMB Associates ................................................................................................................................. 57

Joint Ventures .................................................................................................................................... 64

Collaborations ................................................................................................................................... 70

IMBcom Pty Ltd ............................................................................................................................... 72

Developing Excellence ....................................................................... 74

Office of Public Policy and Ethics .................................................................................................... 75

IMB Publications 2001 ..................................................................................................................... 76

IMB Seminars ................................................................................................................................... 84

IMB Graduate Program ..................................................................................................................... 88

The Institute ....................................................................................... 90

Organisational Structure .................................................................................................................... 90

IMB Board ........................................................................................................................................ 91

IMB Scientific Advisory Board ........................................................................................................ 91

Staff and Students ............................................................................................................................. 92

Financials............................................................................................ 98

How can we help you? ..................................................................... 100

Table of Contents

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The Institute for Molecular Bioscience (IMB) wasofficially established in 2000.

Based at The University of Queensland, the IMBincorporates the Centre for Molecular and CellularBiology, the Centre for Drug Design andDevelopment, the ARC Special Research Centrefor Functional and Applied Genomics, and theheadquarters and Brisbane division of theAustralian Genome Research Facility, as well assignificant components of the AdvancedComputational Modelling Centre and the Centrefor Microscopy and Microanalysis.

Recognised nationally and internationally, theIMB is already one of Australia’s leading researchinstitutes and a major centre for molecularbioscience research.

It links leading edge genomic discovery andbioinformatic facilities with state-of-the-artresearch to better understand human and animalbiology, and to develop new pharmaceuticals,diagnostics, nanotechnologies and diseasetherapies.

Research at the IMB includes the genomic andgenetic analysis of mammalian development andcell biology, as well as structural analysis of keyproteins and the discovery of new chemicals thatmay interact with these proteins as the basis fornew pharmaceutical development aimed at cancer,inflammatory and infectious diseases, and a rangeof common human diseases.

The IMB is a core partner in two CooperativeResearch Centres, the CRC for the Discovery ofGenes for Common Human Diseases and the CRCfor Chronic Inflammatory Diseases.

About the IMB

Creating operational synergies between research,industry and government, the IMB provides anintegrated environment of excellence thatcapitalises on a spectrum of intellectual andphysical resources, a multi-disciplinary approachand effective links between groups involved indiscovery and those involved in developingpractical applications.

The Institute’s commercialisation arm, IMBcomPty Ltd, was established in March 2000.IMBcom’s mission is to provide a dedicatedvehicle for the commercialisation anddevelopment of IMB’s research and technologies.

From 2002, the IMB will be housed in a new $105million, state-of-the-art 35,000m2 facility,currently under construction at The University ofQueensland, together with the CSIRO and otherresearch organisations, enabling greater scientificinteraction and collaboration.

More than 700 scientists, research students andsupport staff from the IMB, CSIRO andQueensland Department of Primary Industries,will be working in the new complex, making itone of the largest and most innovative biologicalresearch centres in the Southern Hemisphere.

Exploring beyond traditional andnarrow boundaries ensures the IMBcontinues to revolutionise emerging

fields and new discoveriesincorporating the full spectrum of

molecular bioscience.

Leadership

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The IMB is an innovative joint research and development initiative ofThe University of Queensland, the Queensland Government and the Commonwealth Government.

Artist impression of the UQ/CSIRO Joint Building Project currently under construction to house the IMBtogether with the CSIRO, Queensland Department of Primary Industries and other research organisations.

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2001 Highlights

The IMB’s research is a prime example of Australian minds leading the world, and these minds are thecornerstone of the future health and economic growth of Australia. Awards, discoveries and scientificgrants further enhance the reputation and stature of our scientific endeavour, and recognise the dedicationthat these scientists bring to the quest for understanding. Following are highlights of some of the IMB’sachievements during 2001:

In MemoryThe IMB was saddened by the unexpected passingof Dr Toshiya Yamada on 12 May 2001. Toshi’scontributions to modern developmentalneurobiology have now become standardtextbook entries, a legacy very few scientists canclaim. The IMB, with the assistance of theAustralian Neuroscience Society, will establishan annual lecture in Toshi’s honour, as well asdedicate a plaque and an area of the garden in thenew Institute in his memory.

World leader heads Public Policy & EthicsThe IMB appointed Professor Wayne Hall AM asDirector of Public Policy and Ethics Unit at thisimportant stage in molecular bioscience,biotechnology and genetic research. He brings tothe IMB unparalleled experience in relation toethical and social issues raised by the revolution ingenomics, genetics, cell biology and biotechnologyfollowing his 12 years as Executive Officer of theNational Drug and Alcohol Research Centre.

People

Scholars stand outTwo IMB PhD graduates, Dr David Pennisi andDr Michelle Hill, were recognised on the Dean’slist for their watershed PhD theses.

This award recognises those few PhD graduateswho receive unanimously outstanding reportsfrom their examiners’ reports which commendthem on making genuine and substantialcontributions to their field of research.

Co-Directors awardedIMB Co-director Professor John Mattick wasappointed as an Officer of the Order of Australiain the 2001 Queens Birthday honours list.

In presenting the award Queensland GovernorMajor General Peter Arnison AC recognisedProfessor Mattick’s long and distinguished serviceto scientific research in the fields of molecularbiology and genetics, as well as his role in thedevelopment of the IMB into an internationallyrecognised centre of bioscience research anddiscovery.

IMB Co-director and IMBcom CEO ProfessorPeter Andrews won the Entrepreneur of the YearNorthern Region’s Supporter of Entrepreneurshipaward.

Chosen for his innovative drive, ambition,ingenuity and basic hard work in an industrysearching for firsts and discoveries, ProfessorAndrews is one of the leaders to nurture the IMBand stimulate our best young scientists to “taketheir discoveries further than the lab bench”.

Dr Toshiya Yamada15 October 1960 – 12 May 2001

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Research

Researchers scoop the gene poolIMB researchers were awarded the AMPBiomedical Research Awards in both the pre- andpost-doctoral categories for 2001.

PhD student at the IMB Delvac Oceandy won thepre-doctoral category for his research into thegenetic control of Cystic Fibrosis (CF) lunginflammation disease. His results indicated thatrestoration of gene function in the lung epithelialcells can lead to easing of the disease and thatgene transfer technologies may be useful in thedevelopment of new therapies for Cystic Fibrosis.

Dr Uwe Dressel, on a fellowship exchange at theIMB from the German Academic ExchangeService, won the post-doctoral category for hiswork investigating the mechanisms that regulatemuscle development. Understanding thedevelopment of undifferentiated precursor cellsinto specialised tissues such as muscle providescornerstones for the development of therapies tocounter muscle-related diseases.

Awards for IMB researchersThe premier body for bioscience research inAustralia, the Australian Society for Biochemistryand Molecular Biology (ASBMB), recognised theresearch excellence of two other IMB scientists.

Professor David Hume was awarded theprestigious 2001 Amersham-PharmaciaBiotechnology Medal for his distinguishedcontributions to the field of biochemistry andmolecular biology. The Award is intended as atravelling Lectureship and carries an Honorariumand a Medal.

PhD student Julie Dutton was awarded a ASBMBFellowship for her outstanding work on thestructural biology of the toxins from marine snailsand their potential as therapeutics for neurologicaldisorders. Julie also won a Finn World TravelAward from the Protein Society and combinedthese awards to attend the 15th Symposium of theProtein Society in Philadelphia and visit the WistarInstitute at the University of Pennsylvania.

Another win for top research

Associate Professor Bostjan Kobe (pictured abovecentre with the Prime Minister and other awardwinners), a joint appointment at the IMB and theDepartment of Biochemistry and MolecularBiology at UQ, was awarded the 2001 Minister’sPrize for Achievement in Life Sciences atParliament House.

The $35,000 award, presented at the PrimeMinister’s Prize for Science Dinner, recognisedthe ground-breaking contributions AssociateProfessor Kobe has made to world knowledgewith his work on the 3-D structure of proteins.

Commercialisation developmentProtagonist Pty Ltd, a new wholly Australian-owned biotechnology company, was one of fourspin-out companies generated from IMB researchin 2001.

Protagonist is gearing up as a major force tocombat costly medical conditions and to benefitworldwide health following a $3 millioninvestment from Start-up Australia.

The investment by Start-up Australia inProtagonist is tapping into a potential billion-dollar global market with significant social, healthand economic benefits for Australians.

The other IMB spin-outs in 2001 were MimeticaPty Ltd, Nanomics Biosystems Pty Ltd, andKalthera Pty Ltd.

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Amgen awards IMB honours studentIMB student researcher Emily McGhie wasawarded the prestigious Amgen Australia Prize inMolecular and Cellular Biology in 2000.

During the course of her research, Ms McGhieinvestigated how changes in protein function canbe achieved without altering the original genomesequence. The project was an example of theincreasingly interdisciplinary nature of today’sbioscience research.

(left-right) Amgen’s Christine Culverhouse,Federal Member for Ryan Michael Johnson,

and IMB’s John Mattick presentedEmily McGhie with her prize.

CRC up and running against inflammationA new cutting-edge research centre with state-of-the-art technology started operating in July2001 to help better understand and fightinflammatory diseases and thus improve thehealth of Australians.

The Cooperative Research Centre (CRC) forChronic Inflammatory Diseases combines theformidable expertise of research groups from theIMB, the University of Melbourne, MonashUniversity, and multinational drug companyAstraZeneca. The focus of the Queensland node,headed by IMB’s Professor David Hume, is“systems biology”, in which researchers attemptto use the knowledge gained from the humangenome project to identify all the componentsneeded to make a biological system work.

Events

State of playBiotechnology analyst Dr Daniela Bellomo fromIMB’s commercialisation arm IMBcom, made apresentation to Queensland Parliament aboutsome of the commercial benefits of the biosciencerevolution, including hundreds of new jobs.

The information in the genetic code will impactenormously on health and medical research butpossibly the biggest gains will come in areasbeyond these applications representing only thetip of the iceberg.

IMB hosts world’s leading genomic scientistThe IMB hosted senior members of government,heads of research institutes, and key individualsfrom CSIRO, the biotechnology industry and theinvestment community from around Australia atvarious functions throughout 2001, including anevent that featured President of Celera GenomicsDr J. Craig Venter.

Dr Venter’s event coincided with the publicationof the human genome in the prestigious USjournal Science.

The event was a rare opportunity to hear theworld’s foremost expert discuss the project thatrevolutionised bioscience research worldwide.

(left-right) IMB’s John Mattick withCelera Genomics’ Craig Venter.

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Grants

IMB awarded $7.7 millionIn the September 2001 round of ARC grants, IMBresearchers were awarded over $7.7 million incompetitive research funding. Spread over fiveyears, the funding will support research projectsand infrastructure costs across a broad range ofinter-related research interests ranging fromproteomics, to developmental biology.

Some of the successful projects in this roundincluded:

• $735,000 to establish a world class proteomicsfacility allowing the investigation of howproteins control gene expression, theorganisations of proteins in cells andidentification of proteins that may be potentialdrug targets.

• $550,000 for a robotic nuclear magneticresonance spectrometer that will aid the rapidcharacterisation of drug-protein interactionsand in the discovery of new drugs oragrochemicals. This machine will acceleratethe rate of discovery of the structure andfunction of proteins leading to thedevelopment of new bio-active molecules.

• $1.55 million over five years to create smallmolecules that mimic protein structure, withthe potential to develop new drug leads andbiological tools to better understandbiological processes.

• $2.3 million over five years was earmarkedfor research into the development of potentialdrugs from the venom of Australian coneshells, particularly focussing on peptides thatselectively affect the nervous system.

• $1.75 million over five years to continueresearch into genetic mechanisms controllingsexual development of embryos.

In brief:

The IMB Board was appointed and held first meeting in October 2001.

The IMB Scientific Advisory Board was appointed and their first meetingwas scheduled for March 2002, coinciding with the inaugral IMB ScientificSymposium.

Construction of the UQ/CSIRO Joint Building Project, which will house theIMB together with the CSIRO from late 2002, continued during the year.

The IMB received notification in December that it had secured a major coupto host the prestigious Intelligent Systems in Molecular Biology 2003conference. The Brisbane event will be the first time the ISMB conferencehas been held outside North America or Europe. It is anticipated that theconference will inject around $3 million into the Queensland economy overthe four day event with more than 1800 world leaders in computationalbiology and bioinformatics attending.

In 2001 PhDs were awarded to four students: Iain Sharpe, Gos Schepers,Ylva Strandberg and David Wilson and a Masters to Nikolai Sokolenko.

Several IMB staff were recognised with fellowships or promotions in 2001:

• ARC Australian Professorial Fellowships to David Fairlie and PeterKoopman

• NHMRC Fellowships to Sean Grimmond, Michael Waters and CarolWicking

• Rick Sturm promoted to Principal Research Fellow

• Greg Bourne, Robert Reid and Stephen Love promoted to SeniorResearch Officer

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The IMB Board was appointed in 2001 and is comprised of senior members of the University, IMB Directors and a majority ofindependent external members who are prominent individuals from research, industry, the professions, and the community who will guide

the progress and support the mission of the IMB. Members of the Board held their first official meeting on 1 October 2001.

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Chair’s Report

The Institute for Molecular Bioscience (IMB) has enjoyed another remarkable year. Established in 2000by the merger of two major University of Queensland research centres, the IMB has built a stronginternational reputation for excellence in research and productive industry collaboration.

The Institute was set up with financial support from the Queensland and Australian Governments as wellas a private donor, and in 2003 will be based in a new $105 million complex at St Lucia, Brisbane,together with Commonwealth Scientific and Industrial Research Organisation (CSIRO) laboratories.

Apart from generous financial assistance, the key to the IMB’s success has been its dedicated and talentedstaff, and I would like to give particular praise to the Institute’s co-directors Professor John Mattick andProfessor Peter Andrews. Under their leadership, the Institute has developed a spectrum of research fromgenomics through developmental and structural biology to medicinal chemistry and preclinical biology.

This has been underpinned by major University investments in bioinformatics and computational biology,including the establishment of a new supercomputing facility on the St Lucia campus.

The Institute is also committed to contributing towards the economic growth of Brisbane and Australia,and has helped in the formation of a number of significant spin-off companies.

The broad strategic direction of the Institute is overseen by an IMB Board, comprising key internationalscientists and industrialists, as well as the IMB’s co-directors, senior University of Queensland executivesand representatives of the Queensland Government. The board, which is assisted by high-level Scientificand Business Advisory Committees, held its inaugural meeting on 1 October 2001 and will meet twiceper annum.

In welcoming board members to this first meeting, I noted that the IMB was the single most importantinitiative in the recent history of The University of Queensland. Furthermore, the IMB is paving the wayfor related initiatives in the new sciences in the fields of bioengineering and nanotechnology.

Through its high-quality research, industry collaboration and links to other important initiatives, the IMBis consolidating its position as a leader in the biosciences.

Professor John HayUniversity of Queensland Vice-Chancellor

Chair, IMB Board

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Co-director’s Report

This year is the second of the IMB, in which we have seen further integration of the research interests ofthe Centres that came together to form the Institute. The IMB is unique in Australia in that it is a systemsbiology institute which brings together genomics, genetics, developmental biology, cell biology, structuralbiology and chemistry, with a strong underpinning of bioinformatics and computational biology. Ourintention is to create a multidisciplinary environment that can attack the future challenges in biology,especially to understand how genotype affects phenotype, and to use this information to generate newunderstanding and new applications.

Biological science is undergoing rapid change. The advent of the genome sequences of the human, mouse,fruitfly, nematode and yeast, and of a large number of bacteria and archaea, is revealing the geneticprogramming and molecular components that underlie the diversity of life, and which will need to beunderstood and re-built into an increasingly coherent picture of how life works, and what affects individualvariation, including susceptibility to disease. We not only need to understand the molecular details ofdifferent cellular processes and functions, but also start to integrate this information into a larger frameworkof the genetic and molecular networks that operate in the differentiation and development of complexorganisms. This is a huge challenge, and one that will occupy at least the next generation of biologicalscientists. It will also require new engagement with the physical and informational sciences. The IMB isbuilding its infrastructure and linkages to enable it to address these issues. Through the ARC SpecialResearch Centre for Functional and Applied Genomics, and in partnership with other laboratories at UQand other institutions, we have established a range of facilities that will allow an increasingly seamlessand efficient analysis of the information. We have expanded our bioinformatics infrastructure and transgenicfacilities, and established new microarray and proteomics facilities, with some of the most advancedequipment in Australia. We have also established large-scale protein expression facilities, which willvastly improve the numbers of proteins that we are able to characterise, both structurally and functionally.We have also, among other things, become a partner in a new Cooperative Research Centre for ChronicInflammatory Disease. Most importantly, we have made a number of important discoveries during 2001,many of which are described in the research profiles and in the publications listed in this report.

The IMB’s new building will be completed later this year, and will form part of a large complex beingconstructed in conjunction with CSIRO. The facilities within it are outstanding and I would like to takethis opportunity to congratulate our Deputy-Director, Ian Taylor, as well as Peter Sampson from theUniversity’s Property and Facilities section, and Mark Roehr from Daryl Jackson Architects, for havingplanned an outstanding research facility, which will become one of the most important in Australia. Iwould also like to once again thank the University of Queensland, the Federal Government, CSIRO, ourprivate benefactor, and the State Government for their support for the construction of the complex, andthe State Government for their provision of secure core operating funds that is allowing the Institute todevelop innovative programs and to attract the best researchers in the world to Brisbane.

I would like to thank my Co-Director, Peter Andrews, who has taken responsibility for the commercialdevelopment of the Institute’s activities while I oversee the research, and we jointly set strategic directions.This has been now a longstanding partnership of great strength and great enjoyment. I also commend ourresearch staff, support staff and postgraduate students again for their efforts, support and achievementsthis year. We have now established the Board and Scientific Advisory Board of the Institute, whose membersare all prominent and highly experienced individuals of international stature, and we are grateful forgiving of their valuable time to provide governance and guidance.

Finally, it is my sad duty to report the death in early 2001 of one of the IMB’s Group Leaders, Dr ToshiyaYamada. Toshiya was one of the most influential neurobiologists of his generation, with an outstandinginternationally reputation. His loss was a great shock. We will establish an annual lecture as well as aplace in the Institute garden in his memory, and once again extend our heartfelt condolences to his family.

Professor John Mattick AOIMB Co-director

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Co-director’s Report

Like John Mattick, I’ve given so many talks on IMB this year that I can do it in my sleep, and probablyhave. Colleagues throughout academia, industry, government and now the investment community areincreasingly fascinated by our plans to span the spectrum from gene to drug, from bench to business,and most are keen to hear how we are going about achieving them.

Of particular interest to many is our thesis that by focussing on outstanding research, great developmentopportunities will follow. That thesis is already proving to be strongly supported by the facts.

During 2001 for example, three of our spin-out companies – Xenome, Promics and Protagonist – attractedfirst or second round venture capital investments of between $3 and $4.5 million. Xenome appointedProfessor Tony Evans as its foundation CEO, and Dr Mark Smythe accepted a 50% appointment asCEO/CSO of Protagonist. Three other spin-outs – Nanomics, Mimetica and Kalthera – were established,and are currently considering offers of seed capital.

The Institute’s external collaborations also continued to expand with the successful establishment ofthe new CRC for Chronic Inflammatory Diseases of which the Queensland node is led by our ProfessorDavid Hume, and the formation of a major alliance with Japanese trading house Itochu. Other keyresearch alliances with CSIRO, QIMR and the Australian Institute of Marine Science have continued toprogress, and have also proved to be key factors in our involvement in several biotechnology Centre ofExcellence applications, the outcomes of which will be known in 2002.

All of these spin-outs and alliances are based on what was originally pure, curiosity-driven research,albeit undertaken by researchers with a strong interest in creating ultimate commercial outcomes. Tothat end, IMB’s commercialisation arm IMBcom is working closely with the Institute’s researchers toidentify projects with commercial potential, and helping them to locate the capital and other resourcesrequired to further develop their research.

The upshot of all of this is that we are meeting and exceeding the various key performance indicators –jobs created, spin-offs established, income generated – that underpin the investments by the QueenslandState Government in the capital and operating costs of the Institute. Those of you who live in Brisbane,or who have had the opportunity to visit us over the past year, will also have seen the most tangibleevidence of this investment – the magnificent building under construction at the entrance to the Universityof Queensland.

Last, but far from least, congratulations to my friend and partner, John Mattick, on the award of theOrder of Australia (AO) in 2001 for his long and distinguished service to scientific research in the fieldsof molecular biology and genetics, as well as his role in the development of the IMB into an internationallyrecognised centre of bioscience research and discovery.

The Institute that we are now building has been John’s dream for the past seven years, and it is a delightto see it coming to fruition.

Professor Peter AndrewsIMB Co-director

IMBcom CEO

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IMB Boardas at 31 December 2001

Chair

Prof. John HayVice-ChancellorUQ

Professor John Hay, Vice-Chancellor andPresident of The University of Queensland sinceJanuary 1996, has extensive experience inAustralian universities in academic, administrativeand leadership roles.

The University of Queensland was named asAustralia’s 1998-99 University of the Year by theGood Universities Guides for outstandingoutcomes for graduates.

Professor Hay has published widely in the fieldsof English literature, Australian literature, literarytheory, scholarly bibliography and education withsome 18 volumes and numerous research papersto his credit.

In 1987, he became Dean of Arts at MonashUniversity where he also established the nationalKey Centre for Australian Studies. In 1988, hewas appointed Senior Deputy Vice-Chancellor atMonash, with principal responsibility for strategicplanning.

He also played a key role in Monash’s majorgrowth and mergers during 1989-91.

In 1992, Professor Hay was appointed Vice-Chancellor and President of Deakin University inVictoria and directed the transformation of a small,regional institution into a large, multi-campusuniversity with 30,000 enrolments.

In 1995, Deakin was named University of the Yearby the Good Universities Guides for use oftechnology in teaching undergraduate education.

In 1997, Professor Hay was appointed to the Boardof the Queensland Performing Arts Trust by theQueensland Government.

Deputy Vice-Chancellor

Prof. Paul GreenfieldDeputy Vice-ChancellorUQ

Professor Paul Greenfield was appointed DeputyVice-Chancellor (Research) at The University ofQueensland in October 1997. He has wideprofessional and academic experience both inAustralia and overseas. He has worked as aconsultant for numerous national and internationalcompanies and government agencies in the fieldsof biotechnology, wastewater management,environmental management and project evaluation.In addition, he has served on a number of nationaland international committees, including theNational Greenhouse Advisory Panel which hejoined in 1994, and the DETYA High PerformanceComputing Interim Executive Board ofManagement. He is also currently chair of theScientific Advisory Committee overseeing the $5.2million Moreton Bay and Brisbane RiverWastewater Management Study.

Professor Greenfield’s research is internationallyrecognised, in terms of ability to attract fundingand publish significant output. He has authoredover 180 journal publications, 120 conferencepublications, 3 patents and over 20 invitedinternational (keynote/plenary) addresses. Hecontinues to be an active supervisor for PhDstudents.

Professor Greenfield is currently a Fellow of theAustralian Academy of Technological Sciencesand Engineering (FTSE), the Institution ofChemical Engineers (FIChe), a Member of theInstitute of Engineers, Australia (MIEAust), anda Member of the American Institute of ChemicalEngineers (MAIChE). In 1995, ProfessorGreenfield’s contribution to his field wasrecognised when he was presented the ChemecaMedal, awarded jointly by Institution of ChemicalEngineers & Institute of Engineers Australia forOutstanding Contribution to the Profession, andagain in 1998, when he was named as the Instituteof Engineers ‘Engineer of the Year’.

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IMBcom representative

Prof. Peter AndrewsCo-Director IMBCEO IMBcom

Professor Peter Andrews is Co-Director of theIMB at UQ, and CEO of its commercialisationarm, IMBcom Pty Ltd.

He is also a Director of Alchemia Pty Ltd,Xenome Ltd and Protagonist Ltd, a Fellow of theAustralian Academy of Technological Sciencesand Engineering, and President of the AsianFederation of Medicinal Chemistry.

Professor Andrews is an active promoter of thebenefits of closer interactions between publicsector research organisations and industry, and hasbeen at the forefront of initiatives to foster thedevelopment of new industries based onAustralia’s high quality research.

Professor Andrews has worked in the field of drugdesign for over 25 years, establishing researchlaboratories at ANU, Victorian College ofPharmacy, Bond University and University ofQueensland.

Outcomes from these laboratories include thedelineation of the structural requirements of manyclasses of CNS-active drugs (ANU, VCP), thedesign of the Biota flu drug, Relenza (VCP), thedevelopment of heuristic methods for the analysisof drug-receptor interactions (VCP), and thediscovery of potential antiviral and analgesicdrugs currently in preclinical and clinicaldevelopment (UQ).

His personal research interest is in the structureand function of biologically active substances,with a particular focus on the computer-aideddesign of novel pharmaceuticals.

IMB representative

Prof. John Mattick AOCo-Director IMBDirector AGRFDirector ARC SRC forFunctional and AppliedGenomics

Professor Mattick was responsible for thedevelopment of the IMB and is Co-Director ofthe Institute with Professor Peter Andrews.

In 1988 he was appointed the FoundationProfessor of Molecular Biology and Director ofthe Centre for Molecular Biology andBiotechnology at the University of Queensland.The Centre was subsequently designated a SpecialResearch Centre of the Australian ResearchCouncil (1991-1999) and was re-named theCMCB, with its primary focus being the moleculargenetics of mammals and their diseases, includinggenome mapping, gene regulation, developmentalbiology and cell biology.

He was responsible for the development of one ofthe first recombinant DNA-based vaccines, andwas the recipient of the 1989 Pharmacia-LKBBiotechnology Medal from the AustralianBiochemical Society, and the inaugural (2000)Eppendorf Achievement Award from the LorneGenome Conference. His current researchinterests are in the genetics of bacterialpathogenesis, and the role of non-coding RNAsin the evolution and development of complexorganisms. He has published over 100 scientificpapers.

Professor Mattick is also, among other things, amember of the Australian Health EthicsCommittee and the Research Committee of theNHMRC. He is a foundation member of therecently established International MolecularBiology Network (Asia-Pacific), was a foundationmember of the Board of ANGIS (the AustralianNational Genome Information Service) from1991-2000 and is currently a member of the Boardof the Australian Proteome Analysis Facility. Heis a member of the Queensland BiotechnologyAdvisory Council and on the Scientific AdvisoryBoards of several institutes nationally andinternationally. He was appointed as an Officerin the Order of Australia in June 2001.

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International Scientist

Prof. Frank GannonExecutive DirectorEuropean MolecularBiology Organization(EMBO)

Since 1994, Frank Gannon has been the ExecutiveDirector of the European Molecular BiologyOrganisation (EMBO) in Heidelberg, Germany,and also Senior Editor of EMBO Reports,Associate Editor of the EMBO Journal and amember of the Governing Body of E-Biosci. Heserves on a number of scientific advisory boardsat institutes throughout Europe.

Prior to his appointment to EMBO in 1994, heobtained a Bachelor of Science from the NationalUniversity of Ireland, Galway in 1970, a PhD fromthe University of Leicester, England in 1973, wasa post-doctoral fellow at the University of MadisonWisconsin from 1973 to 1975, and Chargé deRecherche in the University of Strasbourg from1975 to 1981.

From 1981 to 1994, he was Professor ofMicrobiology, Director of the BiotechnologyProgramme and Director of the NationalDiagnostics Centre at the National University ofIreland, Galway.

He maintains an active laboratory that carries outresearch on the Estrogen Receptor Gene and isincreasingly involved in the overall topic ofelectronic publication in the Life Sciences.

Among other positions, Professor Gannon is anAdvisor to the Asia Pacific Rim InternationalMolecular Biology Network (IMBN); Member ofthe Scientific Council of the Stazione Zoologica,‘Anton Dohrn’, Naples; Member of theInternational Advisory Board on the InternationalInstitute for Molecular and Cell Biology, Warsaw;Advisory to Ibero-American Molecular BiologyOrganisation; and Coordinator of EuropeanBiotechnology Node for Interaction with China.

Biotechnology IndustryRepresentative

Dr Russell HowardCEOMaxygen, Inc. USA

Russell J. Howard is the Chief Executive Officerand a co-founder of Maxygen, Inc. At MelbourneUniversity, Victoria, Australia, Dr Howardreceived his bachelors’ degree in Biochemistrywith honours in 1972 and his PhD on thebiochemistry of marine algae in 1975. Dr Howardbegan his 18 year career in the field of molecularpathogenesis of malaria in 1976 with post doctoralstudies with the immunoparasitology laboratoryof Dr GF Mitchell, Walter and Eliza Hall Institute,Melbourne. These studies continued in 1979 withwork as a visiting Associate at the NationalInstitute of Allergy and Infectious Diseases at theNational Institutes of Health in Bethesda,Maryland. Dr Howard received tenure at the NIH.In 1988 he created the Laboratory of InfectiousDiseases at the DNAX Research Institute ofMolecular and Cellular Biology and continuedwork on antigenic variation in malaria.

In 1992 Dr Howard joined Affymax ResearchInstitute as Vice President and Director of CellBiology, and in 1994 he became President andScientific Director. During this period he led theinterdisciplinary team of 200 scientists workingon the Affymax combinatorial chemistry and drugdiscovery platform while continuing to leadstudies on malaria molecular pathology.

In 1996 Dr Howard became President and ChiefOperating Officer of Maxygen during itsincubator phase. In 1997 Maxygen was spun-outof Affymax. Dr Howard became President andChief Executive Operator of Maxygen in 1998.Dr Howard retains his interest in infectiousdiseases and vaccine discovery and servescurrently as Chairman of the USAID MalariaVaccine Development Program as well as amember of NIH/NIAID malaria vaccinedevelopment committee.

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Business Representative

Ms Helen Lynch AM

Helen Lynch is a Non-Executive Director of ColesMyer Limited, Southcorp Limited, WestpacBanking Corporation and Deputy Chair of OPSMProtector Limited.

She is Chair of the Sydney Symphony Orchestraand a director of CRI Australia Holdings Limited.

From 1995-2000 she was the Chair of theSuperannuation Funds Management Corporationof South Australia.

Helen Lynch had a distinguished career, spanning35 years, in the Banking and Finance Industry atWestpac Banking Corporation including being amember of the Bank’s executive committee.

She left Westpac in 1994 and was appointed aNon-Executive Director of the Bank in 1997.

In 1990 she was the Bulletin/Qantas BusinessWoman of the Year. She was made a Member ofthe Order of Australia in 1994 for services to theBanking and Finance Industry.

Ms Lynch has always been committed to thecommunity, serving as a director of a number ofarts and charitable organisations.

Her current appointments include Director, Centrefor Independent Studies, member of the Board ofthe Garvan Medical Research Institute and amember of the New South Wales RhodesScholarship Selection Committee.

Executive Dean(rotating)

Prof. Mick McManusExecutive DeanFaculty of Biological &Chemical SciencesUQ

In 1992, Professor McManus was appointedFoundation Professor of Pharmacology at theUniversity of Queensland and from 1993-97 wasHead of the Department of Physiology andPharmacology. He was appointed Executive Deanof the Faculty of Biological and Chemical Sciencesin April of 1998. Before moving to BrisbaneProfessor McManus was a National Health andMedical Research Council (NH&MRC) PrincipalResearch Fellow in the Department of ClinicalPharmacology at Flinders University in Adelaide.He was initially trained as a pharmacist at CurtinUniversity of Technology and then earned his PhD.in biochemical pharmacology from the Universityof Western Australia in 1978. Following his PhD,Professor McManus spent two years as apostdoctoral fellow at the Royal PostgraduateMedical School in London and approximately fouryears as a Fogarty International Fellow/Associateat the National Cancer Institute (NIH) in Bethesda,Maryland USA.

On returning to Australia in 1983 he was first anAnti-Cancer Foundation Research Fellow of theUniversities of South Australia and subsequently aNH&MRC Senior/Principal Research Fellow. Hisresearch interests include xenobiotic metabolism(sulfotransferase, cytochromes P450, and flavin-containing monooxygenases) and mechanisms ofchemical mutagenesis and carcinogenesis. He iscurrently a member of the Editorial Board ofPharmacogenetics and the International Journal ofBiochemistry & Cell Biology.

From 1993-96 Professor McManus was aMember of the Board of the Brisbane NorthRegional Health Authority. He has served on anumber of NH&MRC panels: Grant AssignersPanel, CJ Martin and Douglas Wright FellowshipAssessors panels and Regional Grant InterviewingCommittees, and has undertaken a number oftoxicological consultancies for both the federaland local governments.

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CommunityRepresentative

Sir Sydney Schubert

Sir Schubert had more than 40 years career withthe Queensland State Government, including Co-ordinator General and Director General ofPremiers Department between 1976 to 1988.

He was also Chief Executive and Chairman ofDaikyo Group of Companies, Australia and NewZealand from 1988 to 2000.

Sir Schubert is currently Chairman for a numberof Boards, including CRC for The Great BarrierReef World Heritage Area (since 1999), andInternational Marine Projects Activity Centre(since 2000).

He is also a Fellow with the Australian Academyof Technological Sciences and EngineeringHonorary Fellow of the Institution of Engineers.

State Governmentrepresentative

Mr Ross RolfeDirector-GeneralQueensland Dept ofState Development

Ross Rolfe was appointed the Director-Generalof the Department of State Development on 27August 1998 and Co-ordinator General on 20August 1998.

In 1996, he was the Director-General of theDepartment of Environment and Heritage, underthe previous Labour Government.

Mr Rolfe has a background in issues relating toland management, the energy industry and theenvironment.

During the period between 1996 and 1998, MrRolfe’s expertise and knowledge has been utilisedby such companies as Chevron Asiatic, PowerlinkQueensland, BHP - Coal Division, industryassociations and a range of developmentcompanies.

Leadership

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The IMB Board will meet biannually and haveobligations to ensure the Institute remains viable and

effective for the future.

State GovernmentRepresentative

Mr Kevin YearburyDirector-GeneralQueensland Dept ofInnovation andInformation Economy

Kevin Yearbury has some 20 years experience inpublic administration working in the StateGovernment and with Local Governments.

In 1998 as Director-General of the QueenslandDepartment of Communication and Information,Local Government, Planning and RegionalCommunities, he oversighted the preparation ofQueensland’s first Communication andInformation Technology Strategic Plan, the roll-out of a second broadband cable in coastal andregional Queensland, and the development of anIT architecture for the on-line delivery ofGovernment Services.

In February 2001 Mr Yearbury was appointedDirector-General of the new QueenslandDepartment of Innovation and InformationEconomy.

In this capacity he has responsibility forfacilitating the development of science andtechnology infrastructure to attract newknowledge based industries, co-ordinating publicsector investment in Research and Development(R&D) and promoting innovation and theapplication of technology to generate economicopportunities and social benefits forQueenslanders.

Kevin Yearbury is Chair of i.Lab, the QueenslandGovernment sponsored IT incubator, and aDirector of CITEC, the fully commercial IT&Tand information services business owned by theQueensland Government.

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Genomics and Bioinformatics

The interface of biology with mathematics, computer science, and information technology promises a more-quantitativeunderstanding of the complexities of living organisms, and new models for advanced computation. In the IMB’s Genomicsand Bioinformatics Division, we apply computer-based methods to problems in molecular biology and genomics, and developnew approaches and software to investigate complex cellular processes.

ResearchFrom gene discovery

to practical application

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Automated inference of vertical andlateral gene transmission in bacterialgenomes

For more than 130 years, biologists believed thatall genetic information was transmitted “vertically”from parents to offspring. The very few exceptions– as in the spread of antibiotic resistance amongbacterial populations – were seen as extraordinary,highly specialised phenomena.

Within the past few years this orthodoxy has beenturned on its head. Lateral gene transfer – thetransmission of genetic information across, notwithin, genealogical lineages – is now suspectedto be much more common than previouslyimagined.

The evidence remains somewhat controversial, butin the case of many bacterial genomes isincreasingly convincing. If diverse types ofbacteria participate in a common gene pool, theconsequences could be immense throughoutenvironmental science, biotechnology, agricultureand medicine.

We are constructing an automated computer-basedsystem to collect and manage bacterial genomesequences, identify protein families, generatestructure-sensitive multiple sequence alignments,infer phylogenetic trees and find statisticallysupported instances of incongruence among them.

Although designed to search for laterallytransferred genes, the system will also yieldcomprehensive libraries of protein motifs andother information useful in applied areas ofbioscience, including drug design and metabolicengineering.

Applications of Bayesian phylogeneticinference

Relationships among proteins within a family canbe depicted as a branching tree. The bestalgorithms for inferring these trees from sequencedata are NP-hard, i.e. as more sequences are added

Comparative and Computational Genomics

Group LeaderMark Ragan

Senior researchassistant

Ian Bailey-Mortimer

Postdoctoral fellowJosef Panek

Honours studentSteve Mayocchi

Student researcherBrendan Tse

We use advanced computer methods to investigate similarities and differences among genomes and theproteins they encode. Our goal is to make quantitative inferences about how genomes have come tohave their observed contents of genes, how protein families have diversified, and how cellular functionhas evolved.

to the analysis, we can eventually no longer besure of finding an optimal solution – and theongoing high level of international activity ingenomic sequencing ensures a continual supplyof new sequences.

An exciting new approach based on Bayesianstatistics appears able to postpone this point ofincomputability.

We have carried out extensive comparisons ofclassical and Bayesian methods using real protein-sequence data, and are applying both approachesto a particularly difficult question concerning theorigins of animals, fungi and a recently recognisedgroup of parasites called Ichthyosporea.

Archaeal genomics

In July 2001, the Sulfolobus solfataricus genome-sequencing consortium (of which I was a foundingmember) reported in Proceedings of the NationalAcademy of Sciences USA the complete 2.99-Mbpsequence of this therophilic archaean.

Its highly plastic genome contains 200 diverseinsertion sequence elements, non-autonomousmobile elements, evidence of integrase-mediatedinsertion events, and long clusters of regularlyspaced tandem repeats.

Relational database structures forsequence data

The continuing flood of new gene and proteinsequences, together with the appearance of noveldata types (e.g. from expression arrays), make itincreasingly important that we use advanced toolsfrom information science to organise and querygenomic and other molecular sequence data.

In collaboration with Xiao-feng Zhou (InformationTechnology, UQ), I supervised undergraduatestudent Brendan Tse in mapping the data structuresunderlying GenBank.

We will continue this work during 2002, focusingon the human and mouse genomes.

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Rnomics

Group LeaderJohn Mattick

Research officersDerek Kennedy

Rhonda Perriman

PhD studentsJuliet French

Khairina Tajul ArifinLarry Croft

Stefan StanleyBudi Utama

Research assistantKe-lin Ru

Our group is interested in the role of RNA, especially that derived from introns and noncoding RNAgenes, in regulating gene expression in mammals. The vast majority of the transcriptional output ofthe human genome is noncoding RNA. We are examining the systemic role of noncoding RNA in thenetworking and integration of genomic activity, as well as studying different classes of proteins that areinvolved in RNA metabolism.

Noncoding RNAs: the architects ofeukaryotic complexity?

Around 98% of all transcriptional output in humansis noncoding RNA, derived from introns that aretranscribed and processed from protein codinggenes, and from other genes that only producenoncoding RNA, all of which appear to bedevelopmentally regulated. RNA-mediated generegulation is widespread in the higher eukaryotesand complex genetic phenomena like RNAinterference, co-suppression, transgene silencing,imprinting, methylation, and possibly position-effect variegation and transvection, all involveintersecting pathways based on or connected toRNA signalling. We have suggested that the centraldogma is incomplete, and that intronic and othernoncoding RNAs have evolved to comprise asecond tier of gene expression in the eukaryoteswhich enables the integration and networking ofcomplex suites of gene activity. If this is correctthere are three types of genes in the higherorganisms – those that encode only protein (whichare rare), those that encode both protein and eRNA(efference RNAs derived from introns), and thosethat only encode eRNA (derived from the intronsor exons of noncoding RNA genes). Thus, althoughproteins are the fundamental components andeffectors of cellular function, the basis of eukaryoticcomplexity and phenotypic variation may lieprimarily in a control architecture composed of ahighly parallel system of trans-acting RNAs thatrelay state information required for the coordinationand modulation of gene expression, via chromatinremodeling, RNA-DNA, RNA-RNA and RNA-protein interactions. This system has interestingand perhaps informative analogies with scale-freeand neural networks, as well as with dataflowcomputing.

We are exploring this hypothesis by a variety ofapproaches, including structural analysis of majorclasses of RNA-binding proteins, sequenceanalysis to identify potential subnetworks of RNAtransmitters and RNA or DNA receivers byhomology matching, experimental analysis of suchsubnetworks and of the large numbers of yetunstudied noncoding RNAs identified in ESTdatabases, and by computational modelling ofgenetic networks and operating systems,particularly comparing the conventional modelwith the parallel system that we have proposed.

RNA binding proteins

We recently reported the tissue specific expressionof G3BP, an RNA-binding protein that wasoriginally discovered in this lab. Our data also showthat G3BP is involved in signal transductionthrough interactions with rasGAP120. This is oneof the first RNA-binding proteins, shown to connectsignal transduction pathways to RNA metabolism.We have also identified a novel nucleolar proteinwhich is concerned in all eukaryotes, namedNucleolar RNA-associated protein (Nrap) becauseof its in vivo association with rRNA. Our resultssuggest that Nrap is involved in the early steps of45S rRNA processing.

Localisation of Nrap during mitosis. The proteinis associated with nucleoli during interphase, butredistributes to the condensed chromosomesduring mitosis.



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Recording transcriptional programspromoting angiogenesis

Vasculature is essential for all tissue maintenanceand repair.

We are using microarray-based temporalexpression profiling to define the transcriptionalprograms driven by endogenous promoters ofangiogenesis (hypoxia, VEGF family, bFGFs)with the hope of identifying key regulators of theprocess. Such molecules are keenly sort aspotential targets for controlling pathologicalangiogenesis such as ischaemia and tumourangiogenesis.

Reverse transfection: Microarray basedassays of gene function in living cells

Recently, a microarray based, massively parallel,transfection strategy has been described. Unlikeexpression profiling, this technology provides theopportunity to directly assay biological endpointsrather than transcriptional consequences. Briefly,the method works as follows: adherent mammaliancells are cultured on a glass slide that has beenprinted in defined locations with different liposome–cDNA expression vector complexes.

Expression genomicsMicroarray based gene expression profiling has proven very successful in screening large sets of genes(up to 20,000 per experiment) and identifying those that display differential expression in response to agiven stimuli. When a large number of expression profiles are compiled, data-mining tools can be usedto infer the biological role of differentially expressed genes as well as surmise what biological eventswere taking place within a sample.

Group LeaderSean Grimmond

Research officerJoanne Redburn

Research assistantsAlistair Forrest

Chris JohnsRowena CecilDarrin Taylor

UROP studentJessica Mar

Figure 2: Left panel: 3 x 4 Reverse transfection microarray showing localizedexpression of Green Fluorescent Protein (Green) in HEK293 cells. Nuclei have beencounter stained blue to show monolayer of cells over the array. Right panel: Closeup of a spot from a reverse transfection array: Reverse transfected cells expressinggreen fluorescent protein (green), HEK cell nuclei counterstained with DAPI (blue)and carrier showing location of DNA-liposome complex spotted onto the array (red).

Cells are then grown on the surface of the array,creating regions of localized transfectionthroughout a lawn of non-transfected cells. Theeffect of each expression construct can be gaugedby studying the cluster of living cells present ateach spot location.

Pilot efforts using this technology at the IMB (incollaboration with Rohan Teasdale and JennyStow) have successfully assayed sub-cellularlocalization of full length cDNAs from the RIKENmouse clone encyclopedias (see figure 1).

We are now expanding these studies tosystematically test gene function and sub-cellularlocalization in silico predictions.

Figure 1: Two colour overlay of 32,000 elementIMB-V2 microarray.

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Characterisation of novel genesrequired for biogenesis and function oftype IV fimbriae

Type IV fimbriae of P. aeruginosa are filamentsup to several micrometres in length emanatingfrom one pole of the bacterial cell.

One of the functions of type IV fimbriae is tomediate flagella-independent bacterial movementon a solid surface called twitching motility.

From characterisation of a high density transposonmutant library in our lab, over 40 genes have beenidentified to involve in the biogenesis, functionand regulation of type IV fimbriae inP. aeruginosa.

Many of the characterised genes are homologousto genes involved in type II protein secretion andDNA uptake, revealing that each of these is anevolutionarily and structurally related subset of asupersystem which places multimeric complexeson the cell surface.

Additional characterisation of the remainingmutants in the library has found that two novelgenes are required for the assembly and functionof type IV fimbriae.

One is FimX, a DUF1/DUF2 containing protein,which connects environment signals to twitchingmotility. The other is TonB3, which is an ironuptake transporter, but is also involved in fimbriaetransport from cytoplasma to cell surface.

We are also continuing to analyse and annotatethe P. aeruginosa genome sequence which canbe reviewed at http://pseudomonas.bit.uq.edu.au.

Pseudomonas aeruginosa genomics and pathogenesisThe research programs in the Pseudomonas aeruginosa group are concentrated on studying the genesrequired in the biogenesis and function of type IV fimbriae, control of twitching motility and virulencefactors. The role of extracellular DNA secretion in biofilm formation of P. aeruginosa and the genesinvolved in this DNA production are also being investigated.

Characterisation of functional sites ofChpA in fimbrial biogenesis andvirulence factor production

The expression and function of type IV fimbriaeare regulated by a number of signal transductionsystems, including pilS/R, fimS/algR, Vfr(virulence factor regulator) and a complexchemosensory system whose central componentis chpA.

ChpA is the most sophisticated signal transductionprotein yet described in nature, which has sevenCheA-like phsphorylation domains and a CheYlike regulator domain. The eight possible sites havebeen point-mutated to study functionally the roleof the possible individual site in the type IV fimbraebiogenesis and virulence factor production.

Proteomic techniques such as 2D electrophoresisand Ciphergen technology are also beingemployed to characterise the signal transductionpathways controlling virulence factor regulationin P. aeruginosa.

The role of extracellular DNA secretionin biofilm formation

It has been estimated that biofilms are responsiblefor 65% of all infections. Bacteria in biofilms aremore resistant to antibiotics resulting in recurringinfections.

A recent finding in this lab has shown a novelrole for extracellular DNA in biofilm formation.We are in the process of developing moleculargenetic approaches such as transposonmutagesesis to identify the genes regulatingsecretion of the extracellular DNA and furthercharacterising its role in biofilm formation.

Group LeaderJohn Mattick

Research officersCynthia Whitchurch

Ben Huang

PhD studentsScott BeatsonAndrew LeechShannon Walsh

Masters studentClaire Wade



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The reductionist approach to molecular biology hasgenerated large amounts of detailed data about thestructure and function of living cells at the level ofDNA, RNA and proteins, and the interactionsbetween these molecules.

Recent developments in automated sequencing,high-throughput protein-protein interactiondetection and large-scale gene expressiondetermination have increased the amount of dataavailable to researchers exponentially over the lastdecade.

In parallel with the explosive growth in moleculardata has been an increase in the computationalpower that is cheaply and easily available.

The combination of detaileddata and powerful computershas led to the emergence of thenew field of systems biology.

Systems biology attempts to understand and modelcells, organisms and ecosystems as complexdynamic systems, with behaviour and emergentproperties which cannot be predicted from anexamination of the system components.

A particularly interesting area of complex systemsresearch is the study of biological interactionnetworks.

Interactions between biomolecules within a celltake many forms, including protein-proteininteractions and interactions between enzymesand their substrates.

The entire system of interactions forms a discretenetwork within the cell, which can bereconstructed computationally, enablingresearchers to investigate the properties andbehaviour of the network quickly, easily andrepeatedly.

Our research focuses upon characterizing thestructure, function and dynamics of intracellularinteraction networks, using a combination ofcomputational modelling and real biological data.

Complex systems networksOur research is focused upon understanding cells as complex systems. We use computational modellingand analysis to study the networks of biomolecular interactions which occur within cells, and the wayin which the structure, function and dynamics of these networks are related.

We model networks as graphs. Each interactingindividual in the system, such as a protein or otherbiomolecule, becomes a vertex of the graph, andthe interactions are edges between the vertices.

Edges may be directed or undirected, weighted orunweighted, depending upon the system beingmodelled.

The pattern of connectivity in the network, whetherit is ordered, random, or somewhere in between,has been shown to affect its behaviour.

It has recently been shown that many naturallyoccurring, large, complex networks arecharacterized by a pattern of connectivity betweennodes in which the probability P(k) of a nodehaving a particular number of connections, k,follows a power-law, P(k) ~ k-g, often over manyorders of magnitude.

Such networks are referred to as scale-free orsmall-world networks.

A major problem with extrapolating theoretical andcomputational results about network behaviour toreal biological systems is caused, ironically, bylack of biological data.

Although large amounts of data have beencollected about various aspects of cellular structureand functioning, the data collection effort has notbeen targeted towards use in the computationalmodeling of complex systems.

Consequently, the type of data which could be usedto construct biologically plausible network models– for example, data on protein-protein interactions– is incomplete for most organisms, and the datawhich does exist are concentrated on specificmolecules and biochemical pathways suspectedto be of biological and/or medical importance.

We are currently investigating what proportion ofan entire network must be available in order foruseful inferences to be drawn.

Group LeaderJennifer Hallinan

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Biological networks tend to have a modularorganization, with clusters of genes or geneproducts forming relatively highly interconnectedmodules, and fewer connections between modules.

Such modularity arises in the course of evolution,and probably has significant implications for thefunctional dynamics of the network. Particularlyfor networks organized as a collection of suchfunctional modules, it is possible that individualmodules could be studied more-or-less in isolation.

The illustration shows the protein-protein interaction network of the yeast Saccharomycescerveisiae. The subcellular location of the proteins is colour coded.

This is an attractive idea, since biological data fora small number of complete modules may be mucheasier to assemble than data for an entire network.

We are currently developing algorithms for theobjective detection of modules within complexnetworks



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Bioinformatic discovery of new genes,proteins and pathways

The challenge today for medical scientists is toutilise the mass of nucleotide sequence to expandtheir knowledge of the biological processes theyare currently researching.

I have over five years experience at “mining” thiswealth of information for novel sequences usingvarious bioinformatic approaches.

These in silico observations have catalysednumerous new avenues of scientific explorationfor researchers within my laboratory or mycollaborators.

Recent examples of this include:

• defining the Leishmania major GPIbiosynthesis pathway;

• analysing the mouse and human genomesfor novel members of the SOX, SLIT, andSNX protein families;

• prediction of the function of novel genesisolated in subtracted cDNA librariesenriched for developmentally regulatedmRNAs; and

• prediction of the function of novel genesidentified using microarray technology.

Computational prediction of Golgilocalised proteins

The known functions of the Golgi complex includethe sorting, packaging, post-translationalmodification and transport of secretory proteins,membrane proteins and lipids.

Other functions still remainelusive to cell biologists.

Computational discovery in cellular biologyA major advance in the biological sciences over the last decade is the sequencing of the genomes fromdifferent organisms including the human genome. “Database mining” allows for the prediction of thefunctional properties of a new protein based on the information contained within these genomes. Thegoal of my research is to extract this information to open up new avenues of scientific explorationpredominantly within cell biology.

With the goal of identifying novel Golgi proteins,a computational prediction method was developedthat can distinguish the transmembrane region ofa Golgi resident enzyme from that of a proteinwhich transiently moves through the Golgi.

Subcellular localisation signals

A major issue in cell biology today is how distinctintracellular regions of the cell maintain theirunique composition of proteins and lipids.

For these organelles to maintain their functionintegrity, specific resident proteins must beretained while non-resident proteins allowspassage through them. Individual proteins have“signals” that are responsible for their intracellularlocalisation.

My research group is currently in the process ofidentifying such signals on several differentproteins.

In addition, we are identifying novel proteins thatcontain these localisation signals within thehuman genome. Recent examples of this include:

• basolateral targeting of E-cadherin inpolarised epithelial cells;

• identification of a Golgi LocalisationDomain (GLD) on a novel family ofperipheral membrane proteins; and

• identification of an endosomal targetingdomain, termed SNX-PX.

Characterisation of novel humanproteins involved in the endosome toGolgi membrane trafficking pathway:the Retromer Complex.

The endosomal/lysosomal system of mammaliancells is a highly dynamic trafficking pathway thatincludes membrane transport from both the lateGolgi and the plasma membrane.

Group LeaderRohan Teasdale

Research assistantsCameron FleggElaine Thomas

Honours studentsMarkus Kerr

Jenny BennetsCalle Wibom

PhD studentKevin Miranda

Post-doc studentZheng Yuan

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The primary function of endosomes is the sortingand segregation of receptors and ligands, a processthat is necessary for many cellular operations.

The molecular details of protein trafficking andbiogenesis of the numerous sub-compartments ofthe mammalian endosomal/lysosomal system arepoorly defined.

One strategy to identify proteins that function inthe trafficking of proteins from endosomes to theTGN is to characterise human homologues ofproteins that have been experimentally implicatedin endosomal function in other organismspredominantly yeast.

We are currently characterisinga number of such proteinsusing a range of cellular andbiochemical techniques.

Recently, we defined the protein composition ofhuman retromer complex and showed it wasassociated with endosomal membrane.

The characterisation of this protein complexrepresents the major focus of the cellular biologyaspect of my research group.

Identification of proteins involved inthe membrane trafficking in parasites

The Trypanosomatidae comprise a large group ofparasitic protozoa, some of which cause importantdiseases in humans. These include Trypanosomabrucei (the causative agent of African sleepingsickness), T. cruzi (the causative agent of Chagasdisease in Central and South America) andLeishmania.

Parasite survival requires the surface expressionof specific molecules that form protective surfacecoats, mediate specific host-parasite interactionsand allow the parasite to take up essential nutrients.The biosynthesis, processing and surface transportof these molecules that occurs within theintracellular organelles of the parasite secretorypathway is poorly understood.

A recent effort to sequence the genomes of theseparasites provides us with an opportunity toidentify parasite homologues of proteins thatfunction in membrane trafficking.

A recent collaboration between my laboratory andDr Malcolm McConville (University ofMelbourne) has been established to characterisethese proteins.



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Cellular and Developmental Biology

In order to understand the workings of the cell we have a need to bring together genetics and genomics with an understandingof how cells interact with each other to form an organism (differentiation and development) along with an insight into howthe cell responds to its environment (cell biology). The research of this Division covers that spectrum and forms a powerfulcontinuum of approaches, model systems and key scientific questions. Our programs in genetics focus on the use of geneticapproaches to identify genes involved in cystic fibrosis, basal cell carcinoma, sex determination, angiogenesis and melanoma.Studies of differentiation and development have focussed on the development of the central nervous system, cranio-facialstructures, muscle, kidney and gonads. The programs also focus on understanding molecular signalling within and betweencells, and in particular the targeting and trafficking of proteins to specific cellular compartments, including investigatingnovel subcompartments and their roles in transducing signals such as the RAS pathway. As the number of mammaliangenomes which are sequenced begins to climb the challenge now is how to use such information to derive function. In orderto do so an integrated program of research bringing together genetics, cell biology, differentiation and development willprovide an outstanding platform upon which to generate significant insights.

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Comprehensive Gene ExpressionProfiling

In a collaborative program involving ourlaboratory, the RIKEN Genome Sciences Centerin Japan, the Institute for Systems Biology inSeattle, and the ARC Special Research Centre forFunctional and Applied Genomics, we haveassembled a very large set of mouse macrophage-expressed genes for comprehensive geneexpression profiling. The set of genes expressedin macrophage populations is complex and isinfluenced by many different variables. Ourstudies have also revealed that the genotype ofthe mouse also profoundly alters the geneexpression profile under any particular condition,probably reflecting the divergence in innateimmunity between individuals (see Figure 1).

Computational methods are used to identify setsof genes that always track together; so-calledclusters that contain genes that act in the samepathway, or contribute to the same overallbiological response. Macrophage/osteoclastspecific genes, or those that are induced in aninformative manner, many of which have noknown function, are selected for further study aspart of a structural genomics program in

Macrophages and osteoclasts

Group LeaderDavid Hume

Postdoctoral staffIan CassadyRoy HimesKate Stacey

Timothy RavasiMatthew Sweet

Barbara Fletcher Ian Ross

Dimitry OvchinnikovJulie Osborne

StudentsDavid SesterNicole Walsh

Christine WellsTedjo Sasmono

Saleh HasnawatiTara RobertsKate Irvine

Kate SchroderVera Ripoll

Nick Meadows Rebecca McDonald

Chris MooreTamarind Hamwood

Jill Gillmore

Research assistantsStephen Cronau

Greg YoungChristine Mulford

Angela Trieu

Macrophages are large white blood cells that play a central role in host defense, recognising andengulfing potential pathogens and also removing damaged tissue and dying cells in normal developmentand wounds. Osteoclasts, a macrophage related cell type, are the major cell type able to decalcify bone.Improved understanding of macrophage and osteoclast function could be used not only to boost theirnormal functions but also to limit the pathology caused by these cells when their destructive capacity isunleashed inappropriately in inflammatory and infectious diseases.

collaboration with Associate Professor JennyMartin and Associate Professor Bostjan Kobe.

Transcription control in themacrophage lineage

We have worked on delineating the characteristicsof macrophage-specific promoters that directtranscription solely in the macrophage lineage.Our major focus has been on c-fms, which encodesthe receptor for macrophage colony-stimulatingfactor (CSF-1), the major growth factor for cellsof the mononuclear phagocyte lineage.

We have identified the minimal elements, theproximal promoter and a highly-conservedintronic enhancer, required to direct expressionof a transgene specifically to the macrophagelineage. Using this information, we haveproduced mice which express green fluorescentprotein (GFP) in all cells of the mononuclearphagocyte lineage (Figure 2).

In collaboration with Dr Connie Bonifer in Leeds,and Dr Mike Ostrowski in Columbus, Ohio wehave identified a series of candidate regulatorsthat interact with PU.1, a macrophage specifictranscription factor, such as the leukaemia-associated AML1 transcription factor complex,and members of the microphthalmia transcriptionfactor family.

Figure 1. Macrophage gene trees from (A) BALB/cJ and (B) SJL/J strain macrophages treated withInterferon gamma and LPS

Figure 2. Macrophages expressing greenfluorescent protein (GFP) in the skin of a c-fms-EGFP transgenic mouse



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Differentiation of osteoclasts

Osteoclasts derive from a progenitor shared withother mononuclear phagocytes, and share themajor growth factor, CSF-1 (Figure 3).

We have carried out detailed analysis of thepromoter of the osteoclast marker gene, tartrate-resistant acid phosphatase (TRAP), as a model forunderstanding transcription control duringosteoclast-macrophage divergence.

Amongst the transcription factors that interact withthe TRAP promoter, the microphthalmiatranscription factor (MITF) interacts with themacrophage-specific PU.1 factor.

In collaboration with Mike Ostrowski at OhioState, we are searching for other targets of MITFexpressed in osteoclasts.

Detailed gene expression profiling using cDNAclone sets derived from purified osteoclasts isbeing used to identify candidate regulators andgenes restricted to osteoclasts.

These studies have been expedited by the recentdiscovery of cell line systems in which phenotypictransformation towards an osteoclast-likephenotype can be induced.

This system will also allow furthercharacterisation of the role of members of thenuclear hormone receptor superfamily inosteoclast differentiation.

Response of macrophages to CpG DNAand LPS

Bacterial cell wall products such aslipopolysaccharide (LPS), activate macrophagesto become cytotoxic to the pathogen and to secretea range of cytokines which recruit and activateother immune cells.

Microbial DNA is another product capable ofstimulating the immune system.

The ability of the host to discriminate foreign fromself DNA relies on the presence of unmethylatedCpG motifs in bacterial but not mammalian DNA.

Our ongoing studies address many aspects of theresponse of macrophages to bacterial DNAincluding identification of proteins that interactto form the recognition complex for CpG DNA.We have also examined why self DNA does notactivate immune cells.

The lack of activity of self DNA appears to resultfrom a combination of CpG suppression,methylation of CpG motifs that are present, andthe presence of inhibitory motifs within self DNAthat suppress responses to activating sequences.

We are defining the differences between LPS andCpG DNA that may account for the differentialtoxicities of these two stimuli.

Analysis of global gene expression profiles inresponse to LPS and CpG DNA stimulation hasidentified genes that are both LPS- and CpG DNA-specific in macrophages.

In addition we have demonstrated that CSF-1enhances the LPS-induced inflammatory responsebut suppresses the same response to CpG DNA.Thus CSF-1 may contribute to the differentialtoxicities of LPS and CpG DNA in vivo.

Figure 3. Large multinucleated osteoclastsstained for tartrate-resistant acid phosphatase(TRAP) expression

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Our group is primarily interested in the complexprocesses involved in stimulation of glucosetransport in muscle and fat cells.

The major glucose transporter in muscle and fatcells is GLUT4, which is stored inside the cell insmall vesicles, or GSVs, in the absence of insulin.

The presence of insulin stimulates the movementof GSVs to the plasma membrane (PM).

We have attempted to define the intracellulartrafficking routes employed by GLUT4 that keepit inside the cell and allow it to move to the PMwhen insulin is present.

In the absence of insulin GLUT4 carefullynegotiates its way between multiple intracellularcompartments including endosomes (EE and REin Figure 1) as well as the trans Golgi (TGN).

Molecular transportFollowing a meal, sugar enters the body and sends a message to the pancreas causing the secretion ofinsulin, which then travels to fat and muscle cells instructing them to store the sugar for later use.Disruption of this process leads to major diseases such as diabetes and obesity. These types of diseasesare growing at an alarming rate in Australia and our research will help curb this increase.

This cycle serves to prevent GLUT4 from movingup to the PM. Insulin somehow overrides thisintracellular routing, pushing GLUT4 into acircuit that takes it to the PM.

Our group has identified a series of moleculesknown as SNAREs, (depicted in the diagram) thatusher the intracellular GLUT4 vesicles into thesurface membrane allowing them to fuse.

In this way GLUT4 now becomes incorporatedinto the surface membrane where it can mediateits transport function.

Another area we are interested in is the signaltransduction process (Figure 2).

There are two major pathways that are triggeredwhen insulin binds to its receptor on the plasmamembrane. One involves the serine threoninekinase Akt and the other involves a dimericcomplex containing Cbl/CAP.

We are focussing our efforts on trying to establishwhat is downstream of these molecules in the hopethat we will find other molecules that specificallyregulate some of the trafficking steps displayedin Figure 1.

Group LeaderDavid James

Research officersNia Bryant

Jon WhitheadRolan Govers

Ellen Van DammeJuan Carlos Molero

Fiona Simpson

PhD studentsAnnette Shewan

Rachel ShawHeidi Widberg Flanagan

Visiting researcherGeorg Ramm

Research assistantsJason WyethNick Wade

John NormyleAmanda PriorTara Carton

Figure 1

Figure 2 (Bryant et. al.)



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Molecular genetics of organ development

Molecular genetics of sexdetermination

A major area of interest is the genetic control ofmammalian sex determination. Sex determinationis regarded as a paradigm for the study of howgenes control mammalian development, involvinga pathway of gene regulation under the control ofa “switch” gene on the Y chromosome, Sry.

Our group is continuing to study the molecularbiology of Sry in order to understand its role inmale sex determination and the defects that canresult in sex reversal.

We discovered a gene, Sox9, which plays a criticalrole in male sex determination and actsdownstream of Sry; current studies are aimed atunderstanding the molecular and cellular role ofSox9 in this pathway.

We are also searching for other genes downstreamin the sex-determining pathway, using expressionscreening approaches such as microarrays.

Several novel genes have been identified, and weare developing assays to study the functions ofthese genes in the regulation of gonadaldevelopment.

Work in my laboratory is aimed at isolating genes involved in cell differentiation and morphogenesis,and studying their expression, regulation and function in the mammalian embryo. We are particularlyinterested in the foetal period when the major organs of the body are established. These studies willreveal how the complexity of embryonic development is regulated at the molecular genetic level, aswell as how genetic controls go awry in disease states.

Molecular genetics of vasculardevelopment

In collaboration with George Muscat’s group, wediscovered a gene, Sox18, that is expressedtransiently in endothelial cells during vascularformation in the embryo and in the adult.Mutations in Sox18 disrupt vascular developmentand/or function.

We are currently studying the genetics and biologyof the role of Sox18 in vascular development, andexploring the possibility that angiogenesis can bemodulated – for example to slow the growth oftumours, or promote wound healing - byenhancing or suppressing Sox18 activity.

Sox gene function in mammaliandevelopment

As well as providing a point of entry to the sex-determining pathway, the discovery of Sry has ledto the identification of a family of structurallyrelated genes called Sox genes. The Sox gene familycomprises 20 genes in mice, known to be activeduring embryo development in specific subsets oftissues.

We have identified several new members of thisgene family and are examining their roles in mousedevelopment. We are also interested in thephylogeny of these genes, how they evolved, howthey came to assume different roles in the embryo,and how the different SOX proteins achieve theirspecific functions biochemically.

Group LeaderPeter Koopman

Research officersJosephine Bowles

Megan WilsonDagmar Wilhelm

Shuji Takada

PhD studentsKelly LofflerJames Smith

Meredith DownesFred MartinsonGoslik Schepers

Vacation studentOliver Tam

Research assistantsKristy James

Sarah Penning

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Chronic renal failure (CRF) is a devastatingdisease and an expensive one to treat. It isestimated that 60,000 Australians between 12 and74 yrs have CRF.

Each year, approx. 4000 Australian adults will bediagnosed with CRF, costing the health system>$30 million.

Annually, 1500 patients reach end-stage renalfailure (ESRF); 3 times the number of renaltransplant operations performed.

Dialysis is expensive (~$25-45,000/yr/patient) andonly substitutes for the filtration function of thekidney.

The most common cause of ESRF isglomerulonephritis, however the current steadyrise in ESRF rates is primarily due to an increasein the number of people with Type II diabetes.

One in four Australians will get Type II diabetesduring their life and this will ultimately result innephropathy.

In addition, there is growing evidence that personswith a lower number of nephrons per kidney, whichis determined before birth, are more likely to sufferCRF.

Hence, a greater understanding of the processesinvolved in normal kidney development and CRFare critical to the development of new therapeuticstrategies.

This laboratory is focussing on the isolation ofnovel and important genes involved in kidneydevelopment. To do this we are using the genomictechnique of expression profiling where glass

Group LeaderMelissa Little

Postdoctoral staffGemma Martinez

Fiona RaeParimala Vajjhala Lorine Wilkinson

StudentsMichael PiperGabriel KolleGrant ChallenKevin Gillinder

Research assistantDa Ying Wen

Technical supportSelena Boyd

The kidney is a complex but vital organ. It not only filters the blood to produce urine but also regulatesblood pressure, red blood cell production and produces various hormones and growth factors, includingvitamin D. If your kidneys fail, current treatment involves long term dialysis or organ transplantation,both of which have considerable side effects. The projects under way in my laboratory focus onunderstanding how the kidney arises in the first place and what goes wrong to give you renal disease.

Kidney development and disease

microarray chips are used to simultaneouslyanalyse the overall expression patterns of tissuesand identify those genes that change duringdevelopment.

Novel genes isolated from such screens are thenassessed for their importance in kidneydevelopment using the organ culture assays wehave now established.

These organ cultures allow us to screen novelproteins for their ability to direct or hinder normalbranching of the ureteric tree within the kidney oraffect the formation of new nephrons.

There are several key gene projects which havegrown out of this screen. We have isolated severalmembers of the Slit gene family from developingkidney.



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This laboratory has long worked on the analysisof the role of WT1 mutation in Wilms’ tumour andseveral other conditions.

We have shown that while mutated in sporadicWilms’ tumours, WT1 is not mutated in all suchtumours.

While mutated in renal disease, normal functionof WT1 is critical for both kidney developmentand the ongoing function of the kidney after birth.Hence, WT1 is also mutated in several rare renalfailure conditions, including Denys Drashsyndrome, WAGR syndrome and Frasiersyndrome.

We have been involved in understanding how thetiming and type of mutation results in thesedifferent conditions.

The WT1 gene encodes many related proteinswhich must interact to regulate other genes withinthe cell.

We are investigating how this regulatory proteinworks to create a kidney and keep it functioningby examining what genes it regulates, whatproteins and nucleic acids it interacts with and towhat end.

Previously known to be important in developmentof the central nervous system in everything fromflies to mammals, we have shown that these genesalso play a role in mesoderm development and areall expressed in specific areas of the kidney.

We have also isolated a completely novel gene,Crim1, from the developing kidney which encodesa large membrane protein with an ability to interactwith members of the TGFbeta growth factorsuperfamily.

We are now investigating the ability of this proteinto control kidney development and also lens, spinalcord, brain and tooth.

We also focus on the childhood renal tumour,nephroblastoma or Wilms’ tumour. This is one ofthe most common solid tumours of childhood.

Like many cancers, the inappropriate overgrowthof cells in the tumour is due to a loss of geneswhose role in normal development is to directdifferentation rather than cell growth. One of thecritical genes mutated in Wilms’ tumour is the WT1gene.

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One asks why study muscle differentiation at themolecular level, in particular the transcriptional andmechanistic regulation by nuclear hormonereceptors?

Nuclear hormone receptors (NRs) and theassociated cofactors function as ligand activatedtranscription factors that regulate gene expressioninvolved in reproduction, development andmetabolism.

NRs function as the conduit between physiologyand gene expression. Consequently, they regulatecell fate, spatio-temporal gene expression anddifferentiation during development.

Moreover, NRs and cofactors, when misregulatedand/or mutated result in the onset of disease, whichemphasizes the need for achieving a high resolutionview of their function in tissue differentiation.

Furthermore, the importance of NRs in humanphysiology is underscored by the pharmacopeoiathat has been created to combat disordersassociated with dysfunctional hormone signalling.

Twenty of the 100 top sellingdrugs in the USA are directed atnuclear receptor targets andhave annual sales in excess of$5 billion. NRs affect everyfield of medicine, includingreproduction, inflammation,asthma, cancer, diabetes, andcardiovascular disease.

Secondly, skeletal muscle is a major massperipheral tissue which accounts for ~40% of totalbody weight and is a primary site of glucosemetabolism and fatty acid oxidation. Consequently,it plays a very significant role in insulin sensitivityand the blood lipid profile. The heightenedoccurrence of cardiovascular disease, obesity anddiabetes is associated with lipid disorders.

Muscle and nuclear hormone receptorsMy research interests focus on the regulation of mammalian differentiation by protein-proteininteractions involving nuclear hormone receptors and cofactors, and tissue specific transcription factors.These factors mediate the link between genome and phenome, by operating at the nexus of pathwaysthat control tissue specific transcription, cell signalling and cellular differentiation. Specifically, weseek to understand the hierarchical genetic control of tissue specific gene expression and signaltransduction during muscle differentiation, and disease.

Moreover, age and wound-induced musclewasting, cachexia, etc reflect a malfunction in thebalance between regeneration and decay.

The impact of muscle wasting on therapeutictolerance (e.g. ‘statin’ treatment ofhypercholesterolemia patients), morbidity andmortality in patients with AIDS, cancer andchronic disease further underscores theimportance of this tissue. Accordingly, our workexplores the regulatory crosstalk between thehierarchical transcription factors (e.g. myoD,myogenin & Mef2) and nuclear receptorcofactors.

Group LeaderGeorge Muscat

Research officersBrett HoskingUwe Dressel

PhD studentsUdani Abeypala

Mary WangDisnika Abayratna

Paul RohdeJyotsna Pippal

Visiting studentAngelica Figueroa

Conde-Valvis

Research assistantShayama Wijedasa

Figure 1. HDAC7 is constitutively expressed andshuttles into the cytoplasm during cell cyclewithdrawal and myoblast differentiation



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Specifically, we study how the recruitment ofnuclear receptor cofactors that control histoneacetylation, deacetylation, methylation andchromatin remodelling orchestrates the growth anddifferentiation of muscle.

We have demonstrated how nuclear receptorcofactors that mediate acetylation and methylationof specific proteins regulate the transcriptionalcontrol of skeletal myogenesis and contractileprotein specific transcription.

This study demonstrated that protein-proteininteractions involving nuclear receptor cofactors,and muscle specific regulators that modifyhistones operate at the nexus of pathways thatcontrol tissue specific gene expression andhormone signalling.

Secondly, we have also demonstrated how the classI and II Histone deacetylases (targets of anti-cancerdrugs) suppress the activity of MyoD and MEF2in myoblasts, and provided a potential explanationfor the paradoxical findings that these transcriptionfactors are present in undifferentiated muscle(myoblasts).

Figure 2: Defective sub-cellular localisation andcytoplasmic accumlation of MEF2 in rhabdomyosarcomacells. Immunofluorescent staining with MEF2-red andSRC2-green images highlighting aberrant cytoplasmicMEF2 expression in Rhabdomyosarcoma cells.

Thirdly, our studies have elucidated the molecularbasis of transcriptional regulation by the ‘orphan’nuclear hormone receptors in the context ofmuscle development and differentiation.

Current projects include:

• Regulation of mammalian differentiation bylysine and arginine methyltransferases.

• Molecular mechanism and structure/functionaspects of orphan nuclear hormone receptoraction and transcription (e.g. ROR, Rev-erb,Nur77, etc).

• Functional analysis of the oxy-cholesteroldependent liver X receptors (LXR a/b), andthe fatty acid regulated PeroxisomeProliferator Activated Receptors (PPAR a, gand d) in skeletal muscle. LXR and PPARare the major regulators of lipid andcholesterol metabolism.

• Sox 18 and cardiovascular development anddifferentiation.

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Caveolae, small pits in the surface of manymammalian cell types, have been implicated inregulation of cell proliferation, endocytosis, andlipid transport. In addition, caveolae and caveolins,the major proteins of caveolae, have beenimplicated in a number of disease states includingtumour formation, Alzheimer’s disease, andMuscular Dystrophy. Caveolins are involved inregulation of specific signal transduction pathways.It is a fatty acid and cholesterol-binding proteinwhich has been implicated in regulation of cellularlipids. All cells maintain a delicate balance ofcholesterol, through regulation of influx, efflux,synthesis, and esterification, which is crucial tothe correct functioning of the cell. Caveolins havebeen suggested to be vital components ofcholesterol regulation with a role in cholesterolefflux. Our studies have shown that cholesterol isinvolved in organising plasma membranesignalling domains termed lipid raft domains, andthat this process may be regulated by caveolins.Our studies are aimed at understanding the role ofcaveolae in mammalian cells. We have used anumber of tools to dissect caveolae functionincluding dominant negative caveolin mutants,caveolin-1 knockout mice, and novel Ras assaysystems (in collaboration with John Hancock). Inaddition, we have utilised lower eukaryoticsystems, such as Zebrafish (in collaboration withBrian Key, School of Biomedical Sciences), tounderstand the role of caveolae and caveolins indevelopment and in normal cellular function. Invitro studies show that caveolin mutants perturbvery specific cholesterol-dependent signallingpathways and disrupt lipid metabolism. Our in vivostudies have shown a role for caveolins inevolutionarily conserved developmental pathways.

Cell biology of the plasma membraneOur research interests focus on the organisation, dynamics, and functions of the plasma membrane.These studies have shown that the plasma membrane is organised into microdomains with essentialfunctions in signal transduction and lipid regulation. We are studying the function of domains termedcaveolae and their exploitation by viruses.

Our laboratory is particularly interested in the roleof a muscle-specific caveolin family member,termed caveolin-3, which we discovered in 1995.Mutations in caveolin-3 cause a number ofdifferent muscle diseases including rare forms ofLimb Girdle Muscular Dystrophy. We arepresently analysing caveolin-3-interacting proteinsand a novel compartment with which caveolin-3associates in differentiating muscle cells. We arealso studying caveolin-3 point mutationsoccurring in muscular dystrophy. We recentlyshowed one particular dystrophy-associatedmutant of caveolin-3 inhibits signalling throughlipid raft domains and this could underly thedisease condition. Caveolae have also beenexploited by pathogenic agents. We have shownthat Simian Virus 40, SV40, a non-envelopedoncogenic virus, exploits caveolae to entermammalian cells. SV40 binding activates specificsignalling pathways to recruit cytoplasmicproteins and cause caveolae budding. SV40 isinternalised and then enters an apparently noveltrafficking pathway which culminates in virusreaching the endoplasmic reticulum, the cytosol,and finally the nucleus where replication occurs.

By a combination of electron microscopy, lightmicroscopy and microinjection of living cells, wehave identified some of the compartments andmolecules involved in this unusual traffickingpathway. Understanding this pathway could leadto novel strategies for drug delivery or gene therapy.

Group LeaderRob Parton

Research officersPaavo Rahkila

Amanda CarozziSharon ClarkSally Martin

Pierre-Francois MeryAlbert Pol

PhD studentsSusan Nixon

Isabel Morrow

Visiting scholarSebastian Schmitt

Research assistantsRobert LuetterforstCharles Ferguson

Adrian Knight

Figure 1. An isolated mature muscle fibrelabeled with antibodies to two forms of thecaveolar protein, caveolin-3. The differentforms of the protein are labelled in red andblue. The image shows the organiseddistribution of caveolae over the fibre surface.

Figure 2. Isolated mature muscle fibre treated toremove surface cholesterol and labelled in redand blue.



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A major focus of our group is identifying thesignals and messages involved in specifying theformation of the integument. We are studyingseveral genes and their protein products including,Smoothened, Frizzled-3 and Gli1.

Analyis of the Gli1 oncogene revealedalternatively-spliced exons that generate 5' leadersequences with differing translational capacities.

The transcript with the highest translationalcapacity was associated with basal cell carcinoma.

We have also characterised the mouse and humanFrizzled-3 genes and identified severalalternatively spliced variants that are predicted tointeract with each other to modulate Wntsignalling.

A primary function of the epidermis is to protectus from environmental assault as well aspreventing desiccation.

A major keratinocyte protein involved in boththese functions is profilaggrin. This large(>600kDa), abundant protein is expressed late inepidermal differentiation and is thought to regulateskin water content, have innate anti-microbialactivity, modulate the skin’s response to UVdamage and act as a calcium sink.

We have cloned the mouse profilaggrin gene aswell as related genes in both human and mousethat form a large protein family which has not beenpreviously described.

Keratinocytes are characterised by their extensivearrays of keratin intermediate filaments whichform the cytoskeleton of these cells.

Intermediate filament proteins consist of a highlyconserved central alpha-helical domain flankedby non-helical domains of varying size andcomposition.

While the function of the helical domain has beenknown for several years, the role of the enddomains has yet to be fully elucidated.

Molecular genetics and cellular biology of keratinocytesThe skin and in particular, the epidermis provides a barrier that protects us from harmful radiation,environmental toxins, and infection as well as preventing desiccation. We are studying the contributionof individual genes and proteins to the maintenance of healthy skin. An understanding of the molecularprocesses involved will permit a more targeted approach to the treatment of inherited and acquiredskin diseases such as eczema, psoriasis and cancer.

We used fluorescent tags to determine that a subsetof these end domains contain motifs that specifycytoplasmic localization probably throughinteractions with intermediate filaments near thenucleus and microfilaments at the cell periphery.

In a related project we have investigated the motorprotein complement of keratinocytes anddetermined that kinesin is not involved intransporting intermediate filaments.

KRT6a has an unusual expression characteristicfor an intermediate filament gene. The KRT6agene encodes keratin K6a, which is normallyexpressed in the companion layer of the hairfollicle but is induced in outer root sheath andepidermal keratinocytes in response to wounding.

Because of the utility of an inducible promoterfor applications such as gene therapy we haveexamined the promoter of the mouse KRT6a genein transgenic mice.

We found that deletions into the promoter resultedin constitutive expression of the transgene but didnot alter cell type specificity. We have localizedthe cis-elements that mediate inducibilty to region1.5kb upstream of the transcription initiation site.

Group LeaderJoe Rothnagel

Research officerXue qing Wang

PhD studentsJonathan Beesley

Lexi FriendHetsy Hung

Monica KesslerPawel Listwan

Masters studentRina Masadah

Research assistantSeetha Karunaratne

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E-cadherin is a membrane protein on thebasolateral surface of epithelial cells with essentialroles in cell polarity and cell-cell adhesion. It isalso a powerful tumour suppressor and its loss ordysfunction is an early event in many metastatictumours.

Our studies aim to show how E-cadherin is sortedand delivered to and from the cell surface in kidneyepithelial cells and in tumour cells.

We have shown (in collaboration with Alpha Yap),that surface E-cadherin is endocytosed andrecycled via a novel pathway.

Trafficking of E-cadherin between the surface andendosomes in this recycling pathway is regulated,in both directions, by protein kinases.

This work has major implications for how cell-cell adhesion may be regulated in development,in mature epithelial tissues and in cancer.

Protein traffickingOur research is on the sorting, trafficking and secretion of proteins in epithelial cells and macrophages.This work provides insights into how polarized epithelial cells, in normal tissues and in cancers, deliverproteins to their different membrane domains. In macrophages we are identifying the molecules thatregulate the secretion of inflammatory cytokines.

We have also examined how sorting in the trans-Golgi network of epithelial cells allows E-cadherin to be trafficked in a polarized fashion.

In collaboration with Rohan Teasdale’s group, wehave identified the targeting signal in E-cadherinthat orchestrates its sorting and basolateralmembrane delivery.

This is the first, conserved targeting signalformally identified in cadherins and our findingsforetell how cadherins in many cell types aresorted and trafficked.

There are also implications for how other proteincadherins interact with the E-cadherincytoplasmic tail and this is currently beinginvestigated.

We are interested in how transport vesicles budoff Golgi membranes to transport membrane andsoluble proteins to the cell surface.

This process has been reconstituted in an in vitroassay and from this we have identified differentclasses of transport vesicles and we haveexamined the roles of specific proteins inregulating vesicle budding.

This work also makes use of real time imaging tofollow fluorescently-labelled carrier vesicles inlive cells.

Group LeaderJennifer L. Stow

Research officersFiona Wylie

Lubomira Jamriska

PhD studentChristopher Le

Masters studentBo Wang

Honours studentsDaniel Sangermani

David BryantJulia PaganJohn Lock

Research assistantsDarren Brown

Juliana VenturatoTatiana KhromykhShannon Joseph



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Most recently we have shown that regulators ofG protein signaling (RGS) family proteins havean essential role in regulating vesicle budding.

This work contributes to our understanding ofbasic cell processes and also provides means toexperimentally or therapeutically manipulatesecretion in cells. Macrophages are professionalsecretory cells with finely-tuned but little-studiedsecretory pathways.

Our work has focussed on the mechanisms forsecretion of tumour necrosis factor (TNFa) inimmune-activated macrophages.

We have developed a detailed understanding ofthe intracellular trafficking of TNFa.

We have employed novel approaches and assaysto identify immune-responsive traffickingproteins that regulate the post-Golgi transport ofTNFa.

The regulatory molecules we are identifying arepotential drug targets for the future developmentof anti-TNF therapies.

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MC1R alleles determine skin phototypeand skin cancer risk

Pigmentary traits such as red hair, fair skin, lack oftanning ability, and propensity to freckle have beenidentified as genetic risk factors for both melanomaand non-melanocytic skin cancers in high UVconditions. The human melanocortin-1 receptor(MC1R) is a key determinant of the pigmentationprocess and can account in large part for the diverserange of variation in human pigmentationphenotypes and skin phototypes. We have examinedMC1R variant allele frequencies in the generalpopulation and a collection of adolescent dizygoticand monozygotic twins. MC1R allele associationstudies have also been performed using several case-control studies of sporadic melanoma, Basal CellCarcinoma, Squamous Cell Carcinoma, andfamilial melanoma kindreds collected withinAustralia. These studies have shown that threealleles Arg151Cys, Arg160Trp and Asp294His wereassociated with increased risk of all forms of skincancer and with penetrance and age of onset ofCDKN2A mutation carriers in familial melanoma,with a significant heterozygote carrier effect on skinphototype and skin cancer risk. Ultimately, it is thegenetic and chemical assessment of melaninsynthesis not skin colour that will be the bestindicator for skin cancer risk.

Culture of human melanocyte andmelanoblast strains from skin

Melanocytes isolated from human skindemonstrate a limited life span of up to 25 passagedoublings before arrested growth and cessation offurther division. We have genotyped a largenumber of independent neonatal melanocyte cellstrains to study their growth characteristics and tofunctionally test the effects of MC1R receptorvariants on cell physiology in primary cell culture.Melanoblasts are the neural crest derivedprecursors of melanocytes and have not previouslybeen characterised in culture. We have establishedcultures of human melanoblast cells from neonatalforeskins. These cells typically are non-pigmented,and have a triangular cell body with three dendrites,

Molecular genetics of pigmentationMelanocytes produce the melanin pigments responsible for skin, hair and eye colour. Darker forms ofmelanin protect the skin from solar radiation exposure, however melanocytes are also the cell-typefrom which malignant melanoma can originate. We are studying the human pigmentation system tounderstand the genetic basis of cellular differentiation, tissue-specific gene expression and cellulartransformation induced by solar UV light.

similar to the morphology seen for murinemelanoblasts. When transferred to a mediumroutinely used for melanocyte culture, the cellstake on morphology identical to that of normalmelanocytes and become pigmented.

b3 integrin induction of osteonectin inmetastatic melanoma

Cell adhesion is a reversible process required fortissue remodelling but is disrupted during theprocess of tumour cell metastasis. Expression ofthe b3 integrin protein has been found to be criticalfor melanoma cell progression to metastasis,however, the genetic determinants that drive themetastatic process remain to be determined. Asearch for gene expression changes between b3-subunit positive and negative melanoma cellpopulations, using a highly efficient subtractivehybridization method revealed that b3 integrinoverexpression upregulates molecules associatedwith both adhesion and de-adhesion. We havefound that the counter adhesion proteinosteonectin is induced during the progression ofmelanoma cells from non-tumourigenic radialgrowth to tumourigenic vertical growth.Expression of osteonectin was also associatedwith reduced adhesion of melanoma cells tovitronectin, suggesting that melanoma cells canreadily detach from the extracellular substratedespite expression of the vitronectin receptor avb3integrin. Since melanoma cells also secretevitronectin, it appears that the secretion of thesetwo molecules establishes a balance of adhesionand de-adhesion during the invasive process.

Group LeaderRick Sturm

Research officerRichard Newton

PhD studentsBrooke Gardiner

Anthony Cook

Masters studentHelene Johanson

Research assistantsDarren Smit

Wei Chen



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Molecular genetics of human disease

Group LeaderBrandon Wainwright

Postdoctoral staffElaine Costelloe

Brendan McMorranTammy EllisIan Smyth

Research assistantsDominic Lunn

Emily RileyJacqueline Wicks

PhD studentsChristelle Adolphe

Susan GilliesWendy Ingram

Delvac OceandyKaren McCue

Honours studentsKelly Lammerts van Buren

Christine Mulford

Our research group is focused on elucidating molecular pathology of human genetic disease, primarilythrough the analysis of the single gene disoder, cystic fibrosis and through the discovery of Patched, thegene responsible for both the inherited and sporadic forms of basal cell carcinoma of the skin. As aresult of these studies we have a particular interest in the interface between developmental biology andhuman genetics, and in therapeutic strategies such as gene therapy.

Structure/function of the patchedtumour suppressor gene

The patched gene is part of a signalling cascadeconserved from flies to mammals. We discoveredthe Patched gene was mutated in basal cellcarcinoma of the skin and the common humanbrain cancer, medulloblastoma.

In order to further define the function of patchedwe modelled many mutations in vitro in order toexamine their localisation and binding to theligand, sonic hedgehog. We also established thatPatched function can be measured in transfectionstudies through its ability to downregulate a Glireporter gene. In collaboration with Dr Gary Hime(University of Melbourne) some novel mutantshave been over-expressed in the fruitflyDrosophila melanogaster and as a result we haveidentified a region of Patched which appears tobe responsible for transmitting the Shh signal.

Cellular origin of basal cell carcinoma

Transgenic animal studies have indicated thatpatched mutant mice will develop BCC-likelesions. However, it is still not clear which cellsof the skin give rise to basal cell carcinomas.Usinga number of transgenic approaches we have shown,in association with Joe Rothnagal, that direct geneexcision will specifically occur in the keratinocytesof the outer root sheath - the cell type which is astrong candidate for the cellular origin of BCCs.Also, Cre expression under the control of thekeratin 14 promoter has been achieved and thisdirects gene excision throughout the epidermis.Gene targetted mice have been developed whichexcise the Patched gene in the presence of Crerecombinase so that we now know the necessarymaterials to examine the exact cell type whichgives rise to basal cell carcinoma.

The downstream targets of patched/hedgehog signalling

The downstream targets of patched/hedgehogsignalling are largely unknown and play a key rolein differentiation and development.

We have established that the mouse mesoderm cellline 10t1/2 differentiates in response to membersof the hedgehog ligand family and so we haveused this model system to identify a number ofnovel targets of patched/hedgehog signalling.These molecules potentially have application tocommon human cancer and also to studies oftissue growth and repair.

Regulation of the inflammatoryresponse by CFTR

Individuals with cystic fibrosis suffer from lifethreatening lung disease caused by stimulatedcolonisation with the opportunistic pathogen,Pseudomonas aeruginosa (PA). Data nowindicates that in addition to the known biochemicalproperties of the CF gene (CFTR), CF individualshave a CFTR mediated inflammatory defect suchthat they respond massively to inflammatorystimuli. The mechanism via which CFTRmodulates the inflammatory response is not clear,and it is controversial as to which cells in the lungare contributing to the pathology. Our data hasshown that macrophages from CF mice aresensitive to lipopolysaccharide (LPS) stimulation- overproducing a number of inflammatorymediators, including TNF-a and iNOS. We areidentifying the lung epithelial genes regulated byPA infection, which are potential therapeutictargets to prevent the irreversible lung diseasecharacteristic of CF.

Origin of the cystic fibrosisinflammatory response

The cytokine profile of the infected CF lungindicates that both epithelial cells and inflammatorycells may express cell autonomous CFTR-mediateddefects in the inflammatory response. We haveshown that the introduction of functioning CFTRinto the airway cells is necessary and sufficient torestore the inflammatory and pathogen clearancedefects characteristic of CF. These studies havegiven us an indication of what the true targets forsuccessful gene therapy might be.

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Molecular biology of cytokine hormones, growth hormone & prolactin

Group LeaderMike Waters

Research officersGary Shooter

Richard Brown

PhD studentsCatherine Shang

Becky Conway-CampbellWan Yu

Research assistantsDavid GordonKirstin MillardJenny Rowland

Postnatal growth is a complex process involving cell commitment, differentiation, proliferation andapoptosis, and is driven primarily by growth hormone (GH). In the adult GH serves as a regulator forcarbohydrate, lipid, nitrogen, xeno- and endo-biotic metabolism. We are studying the mechanistic basisfor these divergent actions at all levels from activation of the GH receptor to the genome. We also studythe actions of the homologous hormone, prolactin, which regulates breast and ovarian function.

Activation of the GH receptor

The conventional view of receptor activation byhormone is that it results from dimerization ofreceptor subunits by the hormone. However, wenow have good evidence that the receptor existsin a predimerized state, and that the activationmechanism involves a conformational change. Wehave identified a particular structural motif whichalters its shape in response to receptor activation,and which is required for signalling to the MAPkinase pathway within the cell. Furthermore,perturbing the transmembrane helix of the receptorwith a range of modeled mutations has shown thatthere is a more stringent conformationalrequirement for MAP kinase activation than forother signalling pathways.

We have also fully epitope mapped the residueson the extracellular domain of the receptor whichare targeted by an agonist antibody, the only oneof 14 monoclonal antibodies to the receptorextracellular domain to act as an agonist. Thisinformation is being applied to the design of smallmimics and antagonists of GH, and to the creationof more potent animal growth hormones.

In vivo signalling by the GH receptorand the nature of the signal for growth

In vitro studies have defined a number of signallingpathways used by the GH receptor, and thecytoplasmic domains of the receptor used toinitiate these. However, the signalling pathwaysused for promoting postnatal growth are notknown. We have a program to create targetedknock-in mice with particular receptor signallingdomains debilitated so as to define the domainsand pathways necessary for somatic growth. Wecurrently have chimeras for four constructs andgermline transmission for one of these. These willbe used in conjunction with gene arrays to definesets of transcripts which are regulated by thedifferent GH signalling pathways. We recentlypublished the first documentation of protein/peptide hormone (GH) regulated genes usingcDNA arrays.

Direct nuclear actions of the GHreceptor

We have shown nuclear localization of the GHreceptor in many cells, including cancers. Nucleartargeting of the GH receptor sensitizes the cell tothe mitogenic actions of GH. We have shown thatthe extracellular domain of the receptor can actas a transcriptional activator, and have definedcertain co-activators that bind to it.

We are in the process of identifying the genomicsequences which are associated with the receptorin chromatin complexes.

Osteogenic actions of GH and its rolein tooth development

We have shown that GH acts to promote boneand tooth formation in vitro and in vivo, and thatthis correlates with the induction of bonemorphogenetic proteins 2 and 4.

The in vivo roles have been delineated with GHdeficient dwarf rats and GH receptor knockoutand transgenic excess mice.

Signalling crosstalk and the role ofSOCS proteins in regulating tissuesensitivity to cytokines

We have found that the sensitivity of themammary gland to its trophic hormone, prolactin,decreases when the gland fills, and this correlateswith the induction of suppressor of cytokinesignalling (SOCS)-3, which we have shownblocks the ability of prolactin to signal.

Recently we have extended this to show thatprostaglandin F2a, a GPCR which initiatesluteolysis of the corpus luteum in rodents, appearsto do this by inducing SOCS-3, hence blockingthe luteotrophic actions of prolactin.

This represents a new view of howcell sensitivity to cytokines/hormones can be controlled byheterologous non-cytokine agents.



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The identification of genes involved incraniofacial development

A common feature of many human developmentalsyndromes is dysmorphology of the face, the majorfeatures of which derive from the pharyngealarches during early embryogenesis. The aim of thisproject is to use a genomics approach to identifygenes specifically expressed in pharyngeal archesand which are therefore likely to be important inthe development and patterning of the face.Because facial dysmorphology is a commonfeature of human malformation syndromes, weanticipate that many of these genes will also playa more general role in the development of otherorgan systems, and will thus be implicated in arange of congenital disorders. Using the mouse asa model system, we are employing subtractivehybridisation and microarray technology toidentify novel developmental genes. Access tohuman genome sequence information means wecan more readily identify human homologues andinvestigate their role in human disease. To datewe have identified a large number of novel andpreviously characterised genes whose expressionin the developing embryo suggests a role indevelopment of a range of systems.

Regulation of the hedgehog signallingpathway by intracellular traffickingand sterol levels

The hedgehog signalling cascade plays a pivotalrole in embryonic development and tumourformation. There is mounting evidence to suggestthat regulation of hedgehog signalling at the celllevel involves complex trafficking events whichare linked to cellular sterol levels. In collaborationwith Rob Parton and Brandon Wainwright we havedetermined the fine subcellular localisation ofmembers of the hedgehog pathway, in particularthe hedgehog receptor molecule Patched.Employing both immunofluoresence analysis andimmuno electron microscopy studies we havelocalised Patched to endocytic vesicles within thecell.

Developmental genes and human disease

Group LeaderCarol Wicking

Postdoctoral staffLindsay Fowles

PhD studentsEdwina McGlinn

Tim Evans

Honours studentJenny Bennetts

Research assistantsAlisa Poh

Jenny BerkmanKelly Lammerts van Bueren

Defects arising from abnormal embryonic development are a major cause of infant mortality andchildhood disability. In the wake of the vast amounts of information generated by the large scale genomeefforts, we are using genomics techniques to identify novel genes with a role in development and disease.In addition, we are further investigating the functional role of genes which are known to be pivotal toembryogenesis and human disease.

We are further investigating the effects of alteredsterol levels and perturbed trafficking onsubcellular localisation and signalling activity.

Microarray analysis in a mouse modelof limb development

We are using microarray technologies toinvestigate large scale expression differenceswhich result in the polydactyly phenotype seen inthe limb of the extra-toes (XtJ) mouse mutant. Thismutant is a spontaneous mutant for the geneencoding the Gli3 zinc finger transcription factorwhich, together with Gli1 and Gli2, is involvedin mediating the output of the hedgehog signallingpathway. By assessing the large-scaletranscriptional consequences of dysregulation ofhedgehog signalling in the limb of normal versusXtJ embryos, we have the potential to uncover awealth of molecules acting downstream of thehedgehog signal to determine the correctembryonic patterning of the limb. Since hedgehogsignalling is central to the development of an arrayof vertebrate organs and systems, we anticipatethat the results obtained in this study willcontribute to our understanding of vertebratedevelopment in a broader context.

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Our laboratory is interested in the moleculargenetics of neural development in the mouse,chicken and zebrafish embryo.

During normal development, an embryo producesthousands of different types of neurons and glialcells.

As well as developing different functions andmorphologies, neurons must develop at correctpositions within the nervous system and connectprecisely with other neurons or target cells.

We are studying how theseprocesses are controlled atmolecular and genetic levelsduring embryonic development.

Control of neuronal cell identity invertebrate CNS by Sonic hedgehogsignalling pathways

The diversity of neuron types in the developingspinal cord is thought to be partly determined bya gradient of a secreted signalling protein knownas Sonic hedgehog.

Many aspects of this signalling process are, as yet,unknown.

This project investigates the roles of the signallingprotein Sonic hedgehog and its downstreamsignalling pathways in neuronal precursors in thedeveloping spinal cord.

Cell-type specification by transcriptionfactors

In response to differentiation signals such as Sonichedgehog, neuronal precursors and young neuronsbegin to express a variety of transcription factorswhich first act to “specify” the cells.

This specification causes the initiation of a geneticcascade that leads to differentiation.

Molecular genetics of neural developmentThe central nervous system (CNS) is an incredibly complex organ system and is responsible formovement, sensation, memory and learning. In humans, the CNS is also responsible for higher functionssuch as language and consciousness. We are investigating molecules and genes that control thedevelopment of the nervous system in a number of animals. Discovering how genes and moleculesfunction and interact in the nervous system during embryonic development will provide a fascinatinginsight into the processes that generate a functioning nervous system as well as a greater understandingof nervous system disease.

In this project, we focus on several transcriptionfactors whose expression defines unique classesof neurons in the developing spinal cord. We aimto elucidate their role in spinal cord developmentand to characterise the neurons that express them.

To identify the exact function of one these genes,Sox14, we are currently making a Sox14 geneknockout mouse model.

For other genes, we are employing the modernand powerful technique of in ovo electroporationto study their function and regulation in thedeveloping chicken spinal cord.

Functional analysis of vertebrate Slitgenes in developing CNS

The formation of functional neuronal circuits iscontrolled by complex cell interactions mediatedby a variety of secreted signals. We areinvestigating this process by studying the functionof vertebrate Slit genes that are expressed in thefloor plate and notochord, tissues known to becritical in the control of cell patterning and axonguidance in the CNS.

Characterisation of a novel cysteine-rich transmembrane protein Crim-1 invertebrate CNS development

Crim1 is a newly discovered gene expressed inthe floor plate, notochord and developing motorneurons in the spinal cord. The protein productof Crim1 is thought to regulate the functions ofother growth factors in the developing CNSthrough its highly conserved cysteine-rich repeats.

In particular, we are testing potential interactionsbetween Crim1 and Bone Morphogenic Proteinsand other members of the TGF-beta superfamily.

We aim to uncover the functions of Crim1 inneuronal cell differentiation, cell migration and/or survival.

Group LeaderToshiya Yamada

(15.10.60 - 12.05.01)

Postdoctoral staffMurray Hargrave

StudentsAsanka Karunaratne

Gabriel KolleEmma Smith

Joanna Starkey

Research assistantsNing HuangDaying WenIan Wilson



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E-cadherin determines processes as profound anddiverse as epithelial polarity, cell-cell cohesion,motility, and three-dimensional patterning. Givenits diverse functions, a key question is whether thebiological function of E-cadherin is solely due toits contribution to cell surface adhesion, or whetherE-cadherin may also signal to the cell interior uponcell-cell contact. Until recently it was difficult tofind unambiguous evidence that addressed thisquestion. In large part this was due to analyticdifficulties in discriminating between primarysignals that were activated by the cadherinmolecule itself and secondary signals that were dueto adhesion bringing together cell membranes thatcontained other contact-dependent signals. In thepast 12-18 months we have made considerableprogress in resolving this issue.

Using novel experimental systems that combinedpure, specific cadherin ligands with a range of cell-based assays we have identified a primarycadherin-activated signalling pathway thatregulates the actin cytoskeleton.

E-cadherin activates the Rac GTPasesignalling molecule

We have now unequivocal evidence that E-cadherin acts as a signalling receptor. Uponadhesive binding, E-cadherin activates the RacGTPase, a small signalling molecule that controlsfundamental cellular processes,especially the actin cytoskeleton. Inelucidating the sequence of molecularevents leading from cadherin ligationto Rac activation, we identified thelipid kinase, phosphatidylinositide 3-kinase (PI3-K) as a key intermediate.PI3-K is recruited to the cadherinmolecule upon adhesive binding,where it sets up a cascade of signalsthat are necessary for Rac activation.Importantly, activation of PI3-K mayalso control other cellular processes,such as apoptosis and cell growth.

Cell adhesion and morphogenesisMy group is interested in how cell-to-cell contact regulates the patterning and organization of cells intissues. We focus on the cell surface adhesion molecule, E-cadherin. E-cadherin plays in key role inorganizing epithelial tissues, such as the lung, breast, and gastrointestinal tract. Abnormalities in E-cadherin’s function are major contributors to processes by which epithelial cancers become invasiveand metastatic. Our aim is to understand the basic mechanisms of E-cadherin’s biological action, as afundamental basis for elucidating its role in tumor control.

A major part of our work is now devoted to furtheranalysing these signaling pathways, withparticular attention to their potential to control cellmovement and tumor cell invasiveness.

E-cadherin controls actin assembly

It has long been believed that cadherin adhesionmolecules function in cooperation with the actincytoskeleton. Generally, it was envisaged thatcadherins would passive scaffold onto actinfilaments, thereby stabilizing adhesion. Incontrast, my group has now discovered that E-cadherin adopts an instructive, active role to itselfregulate the actin cytoskeleton.

We found that adhesive binding of E-cadherindetermines the site on the cell surface where actinfilaments assemble and, indeed, we demonstratedthe novel finding that E-cadherin interacts withthe Arp2/3 complex of proteins, a major regulatorof actin assembly. We envisage that this processof cadherin-directed actin assembly plays a keyrole in cell-cell recognition during developmentand tissue remodelling. We postulate that thecadherin-activated Rac signalling pathway acts toactivate Arp2/3 and actin assembly.

Members of my group are now pursuing themolecules that transmit the Rac signal to Arp2/3and testing their function in cell adhesion andrecognition.

Group LeaderAlpha Yap

Research officersEva Kovaks

Paige Hilditch-Maguire

PhD studentsAndrew Paterson

Jeanie Scott

Honours studentSahil Parekh

Research assistantsMichelle Pullin

Marita Goodwin

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Structural Biology and Chemistry

Structure-based drug design depends on a thorough understanding of the three dimensional characteristics of importantbiological molecules, including venoms from Australia’s deadliest creatures. Using this information advanced chemistriesare harnessed to determine the roles of proteins and peptides, develop libraries of small molecule mimetics, design andsynthesise reactive and bioactive compounds. Some of these compounds are drug leads that are developed throughpharmacological studies into candidate drugs for clinical evaluation.



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Toxins

In Australia, venomous creatures and their venomsregularly capture the public’s imagination.

We are currently investigating novel componentsfrom the venoms of snakes, spiders, ants and conesnails all of which contain arrays of peptidic toxins.

Typically, these are cysteine rich, selective for avariety of ion channels and receptors, and contain10-80 amino acids.

Some of the highlights in the past year include thestructure and activity of novel omega conotoxinsfrom Conus Catus, the discovery of a leucineswitch in the alpha conotoxin PnIA, the discoveryand structure of a new and highly specific blockerin insect calcium channels from funnel web spidersand the uncovering of two new pharmacologiesfrom the discovery of two new conotoxin classesChi and Rho.

These multidisciplinary programs are carried outin close collaboration with the IMB’s RichardLewis, David Craik and David Adams from UQ’sDepartment of Physiology and Pharmacology.

Considerable new chemistry isbeing undertaken to furtherexplore the nature andimportance of these ‘tightframeworks’, control ofdisulfide bond formation andstructure-function properties ofcircularised conotoxins.

Protein Chemical synthesis

The human genome project and other majorsequencing projects have greatly accelerated theprogress of biotechnology by providing scientistswith a vast array of new amino acid sequences.

Bioactive peptides and proteinsThe research interests of our group include the discovery and total synthesis of toxins from Australia’svenomous creatures, the chemical synthesis of proteins and bioactive peptides, development of newsynthetic and analytical methods, heterocyclic chemistry, proteomics and bioorganic and medicinalchemistry. Special emphasis is placed on determining the structure-function relationships of naturaland / or designed molecules.

An outcome of these initiatives has been anexplosion in the number of gene-encoded proteinsthat are considered novel or important drug targets.

In order to elucidate the biological function of thislarge number of protein sequences, it is necessaryto produce both native and modified peptidesrapidly and in high yield.

Although biological approaches, such asrecombinant-DNA expression methods and nativeprotein isolation are useful procedures forproducing polypeptides, they are frequently timeconsuming and often result in insufficientquantities for further biological and structuralstudies. Furthermore, modifications are usuallylimited to the 20 naturally occurring amino acids.

Chemical protein synthesis provides a rapid and

efficient route for the production of homogenousproteins up to 200 residues that are free ofbiological contaminants.

Our laboratory has been a major player in this fieldand contributed significantly to the recentimprovements in SPPS, together with theintroduction of powerful ligation techniques.

Group LeaderPaul Alewood

Research officersPeter CassidyJens Buchardt

Paramjit BansalJohn Holland

Adjunct appointmentRobert Raven

PhD studentsChristopher Armishaw

Gene HoppingRyan O’Donnell

Scientific officerAlun Jones

Honours studentAaron Poth

Vacation scholarMichael Hines

Research assistantAngela Morrison

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In the past year we have reported the first chemicalsyntheses of Early Pregnancy Factor (related toChaperonin 10) and the thyroid hormone bindingprotein, transthyretin through the introduction ofa new cassette ligation strategy which employs anovel tunable functional group and subsequentthioether ligation – transthyretin was folded andassembled to its tetrameric structure in thepresence of its native ligand, thyroxine, as shownby gel filtration chromatography, native gelelectrophoresis, transthyretin antibody recognitionand thyroid hormone binding.

We also described the first synthesis of humanS100A12 (EN-RAGE) using native chemicalligation. The propensity of S100A12 to dimerisewas examined by electrospray time-of-flight massspectrometry which clearly demonstrated theprevalence of the non-covalent homodimer (M

r

20,890 Da).

Importantly, synthetic human S100A12 in thenanomolar range was chemotactic for neutrophilsand macrophages in vitro.

Solid Phase Chemistry

‘Difficult’ sequences have plagued the history ofpeptide chemistry and continue to pose problemsfor syntheses today.

They are a phenomenon whereby unacceptablylow coupling efficiencies are experienced for aseries of residues during the synthesis, theoccurrence of which is sequence dependent andoften unpredictable.

They are usually a result of intermolecularlyhydrogen bonded aggregates (beta-sheet formation)that do not allow acylation of the N-terminus.

Currently, we are exploring several ways toovercome difficult sequences. These include suchtechniques as the use of

1 highly activated in situ coupling reagents;2 highly efficient coupling methods like in

situ neutralisation;3 polar solvents including

dimethylformamide (DMF) or dimethylsulfoxide (DMSO); and

4 very powerful reversible amide backbonesubstitution.

Recently, we described the use of an activatedacyl transfer auxiliary for hindered ‘difficult’peptide synthesis.

We found ortho-hydroxyl substituted nitrobenzyl(Hnb) groups were suitable N_auxiliaries for thispurpose.

The relative acyl transfer efficiency of the Hnbauxiliary was superior to the 2-hydroxy-4-methoxybenzyl (Hmb) auxiliary with protectedamino acids of varying size.

Significantly, this difference in efficiency wasmore pronounced between more stericallydemanding amino acids.

The Hnb auxiliary is readily incorporated at theN_-amine during SPPS by reductive alkylation ofits corresponding benzaldehyde derivative, andconveniently removed by mild photolysis at366 nm.



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NMR in drug designOur work focuses on the application of NMR spectroscopy in drug design and development. Bydetermining the structures of biologically active molecules it is possible to identify functional regionsof these molecules and use this information to design novel drugs. We have a particular interest in theconcept of stabilising proteins by joining their ends to make circular molecules.

A major focus of our group is on the use of smalldisulfide-rich proteins as leads in drug design.Such proteins often have potent biologicalactivities and, because of their cross-linkingdisulfide bonds, usually have well defined three-dimensional structures that can be determinedusing NMR spectroscopy.

The proteins we study come from animal and plantsources, as well as “designer” proteins we producein the lab. In particular we have been exploringthe bioengineering of circular proteins.

By cyclising proteins and creating embedded knotswithin the structures using disulfide bonds we areable to significantly enhance the stability ofproteins.

Our goal is to overcome current limitations on theuse of conventional proteins as drugs, i.e. theirpoor bioavailability and susceptibility todegradation in vivo.

A company, Kalthera Pty Ltd, has been formed tocommercialise research outcomes relating to aparticularly stable protein motif that we discoveredcalled the cyclic cystine knot.

Two figures illustrating recent structures of cystineknot proteins determined in our group are shown.

One is a trypsin inhibitor from the fruit of thetropical plant Momordica cochinchinensis and theother is a venom component from the Australianfunnel web spider.

The cystine knot arrangement makes these proteinsexceptionally stable and is a common structuralmotif found in defence molecules.

We are currently determining relationshipsbetween structure and activity in a wide range ofcystine knot proteins, including those from plants,cone-snail venoms, snakes, spiders and frogs.

Our cystine knot discovery program involvesfieldwork to many parts of Australia and includedan interesting crossing of the Simpson Desert in2001.

Cystine knot proteins have applications inagriculture as well as in the development ofpharmaceuticals, and in collaboration with DrMarilyn Anderson at La Trobe University we havebeen examining the insecticidal properties of arange of disulfide rich proteins.

The cyclotide proteins discovered in ourlaboratory show particular promise as “natural”insecticides against pest in a range of crop plants.

Group LeaderDavid Craik

Research officersHorst SchirraRichard ClarkNorelle Daly

PhD studentsDaniel BarryJulie Dutton

Manuela TrabiMichael Korsinczky

Karl RosengrenJason MulvennaShane Simonsen

Angela SalimManuel PlanLillian Sando

Masters studentMaria Quimio

Honours studentDavid Ireland

Visiting studentsClaudia Brochado

Bert JanssenSofia Bengtsson

Research assistantShaiyena Williams

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We aim to better understand molecular mechanisms of chemical reactions, biological processes, diseasedevelopment, and drug action. Understanding how molecules interact, how chemical reactions work,and how structure influences reactivity enables us to design and synthesize potent enzyme inhibitorsand receptor antagonists as potential drugs for cancer, infectious diseases, inflammatory disorders andAlzheimer’s disease.

Chemistry and human therapeutics

A key strategic objective has been to mimic smallbioactive protein surfaces that are recognized byother proteins-, DNA- or RNA- during diseaseprocesses.

We have identified peptide conformations that arecommon recognition elements for proteaseenzymes, for classes of G protein-coupledreceptors, and for transcriptional receptors.

One of our synthetic programs has been aimed atdeveloping generic technologies for creating smallorganic molecules to mimic elements of proteinstructure (e.g. beta-strands, beta and gamma turns,beta-sheets, alpha-helices, helix bundles, multi-loop bundles).

Group LeaderDavid Fairlie

Research officersRobert Reid

Martin StoermerJoel Tyndall

Karl HansfordYogendra SinghMatthew GlennPhilip SharpeAndrew Lucke

Thomas RobertsonJohn Abbenante

Chris Clark

PhD studentsDonmienne Leung

Robert SbagliaNikolai Sokolenko

Michael KelsoLeonard Pattenden

Research assistantsRenee Beyer

Warren Oliver

These efforts have resulted in small organicmolecules that are both structural and functionalmimics of bioactive protein surfaces.

Another program involves the design andoptimisation of new drugs using structure- andanalogue- based approaches in conjunction within silico screening and parallel synthesismethodologies.

Figure 1. 2-helical turn of tumour suppressor p53(yellow) bound to oncoprotein MDM2 (blue).

Figure 2. RNA-binding domain of HIV-rev (red).

Figure 4. helix mimic of Zn-binding domain ofthermolysin.

Figure 3. HIV-1 protease inhibitor, a strandmimetic.



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Figure 8. rigid cone-shaped scaffold.

The generic technologies that we have developedto date have led us to successfully create potentand selective inhibitors of aspartic, serine, metalloand cysteine proteases; as well as potent andselective antagonists and agonists of G protein-coupled receptors that span human cellularmembranes and mediate cell signalling.

In our labs multiple classes of small organicmolecules are being developed with potentantitumour activity (inhibiting histonedeacetylases), antiparasitic activity (againstmalaria, giardia, and schistosomal proteases), anti-inflammatory activity (against human cytokines,phospholipases, complement receptors), antiviralactivity (low resistance inhibitors of HIV andDengue proteins), and anti-Alzheimer’s activity(against secretase enzymes). These compounds arein various stages of development.

This has been particularly important for ourresearch on developing non-peptidic agonists/antagonists of GPCRs.

We are also using bioactive small molecules inpharmacogenomics approaches to identifyaberrant gene regulation and protein expressionrelated to untreated versus drug-treated diseasedstates.

Figure 5. parallel loops (pink) on a rigidscaffold (green).

Figure 7. cofactor (yellow) and inhibitor boundto Dengue NS3 protease (grey).

Figure 6. inhibitor bound in active site ofsPLA2.

Figure 9. sPLA2 inhibitor

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We are targeting several important biological areaswith the aim of understanding the structural basisof molecular recognition processes and proteinregulation.

Regulation of nuclear import

Nuclear proteins are synthesized in the cytoplasmand are imported into the nucleus through thenuclear pore complexes. Such transport is directedby special signals, the most common termed thenuclear localization sequences (NLSs).

Importin-alpha is the nuclear import receptor thatrecognizes these NLSs.

The ongoing crystallographic, biophysical andmutagenesis studies are aimed at shedding lighton both regulation and NLS recognition byimportin-alpha, as well as using this protein as astructural framework for engineering new bindingspecificities useful for diagnostic andbiotechnology purposes.

Regulation of phenylalanine hydroxylase

Phenylalanine hydroxylase is a highly regulatedmetabolic enzyme, mutations in which lead to thegenetic disease phenylketonuria.

Structural basis of protein interactionsThe primary research theme in our laboratory involves understanding how the three-dimensional structureof a protein translates into its function, and in particular how proteins interact with each other. Wecombine methods of protein structure determination, particularly crystallography, with computationaltechniques, biophysical methods for evaluation of interactions, protein chemistry and molecular biology.

We are using a combination of mutagenesis,protein chemistry and structural biologytechniques to understand the regulation anddisease-causing mutations associated with thisprotein.

Specificity of signal transductionpathways

The specificity of signal transduction pathwaysstems from specific recognition and regulatoryproperties of proteins involved in these pathways.

The ongoing work involves both experimentalstructure-function studies of signaling moleculessuch as protein kinases, the phosphopeptide-binding FHA domains and a novel class of G-proteins, and computational work aimed atdeveloping bioinformatic tools for functionalannotation based on new protein sequencesobtained by genome sequencing.

In particular, we have recently developedmethodology to predict the substrate specificityof novel Ser/Thr kinases based on sequencesalone, providing a powerful tool for genome-wideanalysis of signaling pathways and identifyingtherapeutic targets.

Figure 1. Substrate binding site in the crystalstructure of protein kinase A. The mainchain of the protein is shown in wormrepresentation, and the determinant residues(magenta), substrate peptide (green,individual substrate residues are labelled(-3) to (+3)) and ADP (blue) are shown instick representation. The protein kinasesurface is shown in transparentrepresentation, determinant residues aremarked 1 to 20, and individual proteinkinase subsites are marked with yellowcircles.

Group LeaderBostjan Kobe

Research officersYing Mei Qi

Ross BrinkworthHelen BlanchardDianne KeoghDouglas Smyth

PhD studentRobert Breinl

Honours studentsSundy Yang

Jong Wei Wooh

Research assistantsDarren Pickering

Len Pattenden



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Solenoid proteins

Many proteins built from repetitive structural unitsare now known to exist, and they are usuallyinvolved in protein-protein interactions and othermolecular recognition events.

We are using the armadillo-repeat proteinimportin-alpha as a prototype structural frameworkto attempt to engineer novel binding specificities.

Leucine-rich repeats are a dominant structuralfeature of proteins involved in plant diseaseresistance.

We are targeting several plant proteins trying tounderstand the molecular basis of plant diseaseresistance.

Targeted structural genomics ofmacrophage proteins

Structural genomics is a large-scale effort todetermine 3D structures of all representativeproteins. 3D structural information is one of themost effective ways to infer protein function. Ourstrategy is to use gene expression informationfrom cDNA microarrays for target selection, andtherefore selectively determine the structures ofmedically relevant proteins via a high-throughputapproach.

The structures will be used to infer biochemical andcellular function and will serve as templates forstructure-based drug design. Macrophage proteinsare of central importance in a wide range ofimmunopathology, including infectious andinflammatory disease, cardiovascular disease andcancer.

Figure 2. Structure of the complex between importin-alpha and a peptide corresponding to the nuclearlocalization sequence from the retinoblastoma protein. Importin-alpha is shown as a ribbon diagram(yellow), and the peptide is colored blue.

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Conus species from which conotoxins are derived,comprise a group of over 500 predatory marinesnails whose venoms have evolved to target fish,worms or molluscs.

The venom of each species contains a unique mixof approximately 100-200 small, constrainedpeptides that typically contain 10-40 amino acidsand 2-5 disulfide bonds. Conotoxins are injectedinto prey to cause rapid immobilisation,principally by targeting voltage-sensitive Na+,Ca2+, and K+, and ligand-gated acetylcholine,serotonin (5-HT3), and N-methyl-D-aspartatereceptors.

Importantly, most conotoxins are also potent andselective as mammalian isoforms of these targets,and the number of new pharmacologies continuesto grow as more conotoxins are characterised.

Conotoxins can be divided into a number of majorclasses based on their pharmacological activityand cysteine frameworks. They are among thesmallest bioactive peptides, and are unusual incontaining a high density of cysteine residues andpost-translation modifications, includinghydroxylation, carboxylation, amidation, sulfationand bromination.

While these features often complicate chemicalcharacterisation and occasionally chemicalsynthesis, they allow highly potent and specificinteractions with ion channels, making themattractive leads in drug design programs.

Our group has broad-ranging expertise in thesynthesis and structural and functionalcharacterisation of these small disulfide-richpeptides that gives us an internationallycompetitive advantage in this field of research.

We conduct multidisciplinary research thatintegrates strengths in peptide discovery,functional characterisation and design approachesthat take advantage of the breadth of opportunitiesoffered by conotoxins and the diversity of channeltypes and subtypes being uncovered through theuse of molecular biology.

Conotoxins are small peptides (mini-proteins) produced by cone snails to rapidly immobilise their prey.These toxins are highly selective modulators of a variety of membrane bound proteins, making themimportant research tools and potential therapeutics. Through a multidisciplinary research programwe are further developing the potential of this interesting class of molecules.

Venom peptides to drugs

The primary goals of this program are to:

• define at a molecular level, the structural andfunctional determinants of ion channel/conotoxin interactions.

• develop new probes that advanceneurophysiological research. This will beachieved by exploring interactions of existingconotoxins with ion channels, and throughthe discovery and design of new conotoxinsusing assay and structure guided approaches.The discovery and development ofconotoxins with the right characteristics ofpotency and selectivity to be useful astherapeutics is of particular interest.

Programs within the group include studies of themolecular basis of interactions of: conotoxins withthe NMDA receptor, mu conotoxins with thesodium channel, omega conotoxins with thecalcium channel, chi conotoxins with thenoradrenaline transporter, alpha conotoxins withthe acetylcholine receptor, rho conotoxins withalpha1 adrenoceptor.

The discovery of new conotoxin pharmacologiesis achieved by assessing the effects of crudevenom or new synthetic toxins on a variety ofcell and tissue assays.

The specific peptide and target are then dissectedusing a multidisciplinary approach.

This work has lead to the discoveryof CVID (AM336) which is inclinical trials for the treatment ofsevere pain, and two new classesof conotoxins (chi and rho) whichare the first peptide inhibitors ofthe noradrenaline transporter andalpha1 adrenoceptor respectively.

Group LeaderRichard Lewis

Research officersDenise AdamsAnnette Nicke

PhD studentsIngrid SchroederShou-hung WangBrett Hamilton

Research assistantsIain Sharpe

Marion LoughnanTrudy Bond

Caroline Ligny-LemaireLinda Thomas



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Adrenaline synthesis

Although adrenaline is best known for its adrenalhormone role in the body’s stress response, it is alsoproduced in significant quantities in discrete regionsof the CNS where it functions as a neurotransmitter.The hormonal role of adrenaline is well known butthe role of adrenaline in the CNS is not. It has beenimplicated in fundamental physiological processesincluding the central control of blood pressure andpituitary hormone secretion.

Other studies link CNS adrenaline with thephysiological effects of ethanolintoxication and theneurodegenerative effects ofAlzheimer’s disease.

Concrete evidence that CNSadrenaline regulates any ofthese processes would makethe neurotransmitter a primecandidate for therapeuticintervention. However the lackof a suitable pharmacological tool to probeadrenaline function without compromising othercatecholamine processes has meant thatadrenaline’s CNS role remains unclear.

In collaboration with Prof Grunewald (KansasUniversity) and Dr McLeish (University ofMichigan) we determined the crystal structure ofPNMT, the adrenaline-synthesizing enzyme. Thiswill be used to design specific inhibitors with whichto probe the role of CNS adrenaline.The crystalstructure of PNMT also allows us to investigate thefunction and evolution of this protein. Comparisonwith the structures of other small molecule MTasesindicates that PNMT may have evolved fromcatechol O-methyltransferase (COMT), amethyltransferase enzyme that also bindscatecholamines and which inactivates adrenalineand noradrenaline by methylating the catecholhydroxyls. The structural comparison alsoprovides evidence for an evolutionary link to athird and much more complex enzyme, glycineN-methyltransferase (GNMT).

Protein structure and drug designOur research focus is the determination of the structures of proteins by protein crystallography, theanalysis of these to better understand protein evolution, function and folding and the use of thesestructures for structure-based design studies. We target the structures of medically relevant proteins,through collaborations within the Institute and with other research teams both in Australia andinternationally. In this report, we focus on two of the several projects in the lab – the adrenaline-synthesizing enzyme PNMT and the SNARE proteins involved in insulin action.

SNARE proteins

In collaboration with Prof. David James, we areinvestigating the SNARE proteins that participatein the insulin regulation of glucose transport inmuscle and fat cells. Insulin stimulates glucosetransport in these cells by triggering the exocytosisof intracellular vesicles containing the glucosetransporter GLUT4 to the plasma membrane. Toensure that the contents of the storage vesicles aredelivered to the correct destination, vesiculartransport must be tightly regulated with high fidelity.

The exquisite specificity iscontrolled by SNARE proteins,a family of cytoplasmicallyoriented integral membraneproteins that mediate dockingand fusion between the vesicleand its target membrane.SNARE proteins on the vesiclemembrane (v-SNARE VAMP)form a SNARE ternary complexwith SNARE proteins on the

target membrane (t-SNAREs Syntaxin and SNAP).Formation of this complex begins a cascade ofinteractions resulting in membrane docking andfusion.

We developed protocols for producing in largequantities the purified forms of the three SNAREproteins involved in insulin regulatedglucose transport, as well as a SNAREregulatory protein Munc18c.

We successfully produced stablecomplexes of the SNARE proteins andare developing a BIACORE assay toinvestigate the specificity and affinityof these interactions.

We intend to investigate the structuresof the SNARE proteins and theircomplexes by protein crystallography.To this end, we recently producedcrystals of the SNARE regulatoryprotein Munc18c.

Group LeaderJenny Martin

Research officersShu-Hong Hu

Fiona McMillanBegoña Heras

Nathan CowiesonRichard Kidd

Professional officerKarl Byriel

PhD studentsMelissa Edeling

Catherine Latham

Honours studentAndrew Pearson

Research assistantsChristine GeeRussell Jarrott

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Combinatorial chemistry and molecular design

Conformational diversity of proteins

Protein structure is currently classified by theshape of the polymeric backbone.

Unfortunately this provides medicinal chemistswith very little information as to the shape ortopography of amino acid side-chains on proteinsurfaces.

We have developed the required algorithms andapplied these to cluster continuous anddiscontinuous protein surfaces.

These privileged side-chain shapes serve as“screens” in an in silico “assay” to identify smallmolecules that match these shapes in a virtualscreening of virtual library approach.

Virtual screening of virtual libraries

We are developing databases of compounds thatencapsulate the wealth of chemical diversityavailable to synthetic chemists.

We are continually optimising adrug design environment thatallows us to identify compoundsin the chemical universe thatmatch the shape of proteins.

New linkers for library synthesis

We have developed a backbone linker and a safetycatch linker for the synthesis of libraries ofmacrocycles, in particular large arrays of peptidicmacrocycles.

We are optimising chemistries for the solid phasesynthesis of large arrays of macrocycles containingunnatural polymers and amide bond isosteres onthese linkers.

We are developing new linkers for the synthesis ofmacrocycles.

Group LeaderMark Smythe

Postdoctoral staffGreg Bourne

Marc CampitelliSteve Love

Tran Trung Tran

StudentsAndrew McDevitt

Doug HortonStephen LongGerald Hartig

Research assistantsJustin Coughlan

Jill Turner

Many biological processes are carried out, or regulated, through protein-protein interactions. Despitetheir physiological significance, they remain one of the most difficult molecular recognition events toinhibit or mimic. Consequently there is a huge pharmaceutical demand for the discovery of smallmolecules that modulate protein function. We are developing methodologies for the discovery of smallmolecule protein mimetics by studying the chemical and conformational diversity of protein surfaces toprovide better candidates for the development of leads for protein-protein interaction targets.

Overcoming difficult macrocyclisationstep

We have developed a novel ring contractionauxiliary that yields monocyclic products that areunobtainable using existing synthetic methods.

We are examining the combination of this strategywith new and existing linkers to provide the solid-phase avenues for the synthesis of highly strainedand novel macrocycles.

Development of potent G-proteincoupled receptor agonists & antagonists

We have synthesised a class of macrocycles thatare unobtainable using existing chemistries.

This class of natural products has shown wideranging biological activities including antitumour,herbicide, antimalarial, opiate agonist andtachykinin NK-2 antagonist activities.

We are exploring this class of macrocycles asorphan ligands for G-protein coupled receptors.

Cytokine Mimetics

Cytokines are a broad class of proteins thatregulate cell-cell interactions under both normaland physiological conditions.

Although the therapeutic use of cytokines is stillat an early stage, current therapeutic indicationsinclude cancer, hepatitis C, multiple sclerosis,growth, asthma and arthritis, and severalcytokines have achieved sales well in excess of$1billion/annum.

We are developing the required design andsynthetic methodologies for the discovery ofmolecules that modulate cytokine function.

Using these structure-based design approaches wehave developed an antagonist of Interleukin-4.



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IMB Associates

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In 2001, the number of staff in the Advanced Computational Modelling Centre (ACMC) grew to 20academics, specialising in high performance computing, advanced visualisation, bioinformatics andcomputational modelling. The ACMC also oversaw the establishment of a new 64 processor SGIsupercomputer and a Virtual Reality Centre at the University of Queensland. Both of these facilitieshave strong use from researchers and students within the IMB.

Specific collaborative projects being undertaken by Kevin Burrage and researchers within the IMB thatuse the Virtual Reality Centre (VISAC) include:

• visual manipulations (including a 3-D fly-through) based on electron micrographic images withFrancis Clark (ACMC);

• an immersive 3-D visualisation of genomic (mouse) microarray data – in collaboration with SeanGrimmond’s micro array group and Steve Jeffrey (ACMC) ;

• immersive 3-D visualisation of a molecular motor (ATPase) based on PDB coordinates and atomicforce-field calculations - in collaboration with Mark Ragan and Thomas Huber (COMBINE).

It is planned to extend this latter project to a collaborative project in 2002 with David Craik’s group onknots and topologies in protein folding.

Kevin Burrage: Computational biology



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Matt Trau: Centre for Nanotechnology & BiomaterialsNanotechnology and Biomaterials focuses on the formation of novel materials and devices for medicaland diagnostic needs. Examples of these include devices for rapid DNA sequencing, genetic screening,and drug discovery. Other devices of interest are artificial tissue matrices for human bone, liver andpancreas tissue. Nanotechnology, the ability to control and manipulate nanometer-sized features ofmatter, is a fundamental tool which is used to fashion such materials & devices.

The overall goal of the research within our centre is to develop biologically related materials and deviceswhich will ultimately improve human health. Our research work is divided into two main categories: (i) Genetic Screening & Drug Discovery devices, and (ii) Artificial tissue matrices for implants into thehuman body. Both of these areas require the preparation of novel materials and devices which have beenfashioned to contain designed nanostructure.

Genetic screening and drug discoverydevicesRapid access to genetic information is central tothe revolution occurring in the pharmaceuticalindustry, particularly in relation to novel drugtarget identification and drug development.Genetic variation, gene expression, gene functionand gene structure are just some of the importantresearch areas requiring efficient methods ofscreening DNA. Within our group we arecurrently developing colloidal devices (ie, devicesthat are comprised of microscopic particles) whichcan be used for rapid DNA sequencing, geneticscreening and drug discovery applications.

Artificial tissue matricesMany human ailments arise as a result of thebody’s inability to fully re-generate damaged tissue(eg, bone, liver, pancreas). Common medicaltherapies in these cases involve the use ofautografts (implants from one’s own body),allografts (implants from cadavers), or othersynthetic (non-biological) materials, each of whichhave their associated problems. Our researchfocuses on developing novel biological,degradable and “living” implants for the humanbody.

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Most animals are arthropods. Yet the genomes and evolutionary genetics of these animals are poorlyunderstood. My research focuses on the ticks of cattle and the lice of humans - parasites that causedisease and economic burdens.

Mitochondrial genomicsMitochondria have their own genomes, and in most groups of animals the order of genes is remarkablysimilar. However, we discovered two extraordinary exceptions: a group of hard ticks, and lice and theirkin. The arrangement of the 37 genes in the mitochondria of these animals has changed so many times itis difficult to reconstruct the evolutionary path of these mitochondria. By studying the exceptions,mitochondria that have changed a lot, we hope to learn about the rule (why the arrangements of genes inmitochondria evolve so slowly).

Nuclear genomicsWe have begun to sequence the expressed genome of Pediculus humanus, a louse that infests people andtransmits 3 bacteria that, together, have killed over 50 million people in the last 100 years.

Molecular epidemiology and evolutionary genetics of parasitic diseasesWe study the epidemiology and genetics of four pathogens that cause diseases: the lice of humans, thescabies mite of humans and dogs, the paralysis tick of dogs, and a single-celled animal called Perkinsusthat kills abalone.

Steve Barker: Evolutionary genomics of arthropods

John Hancock: Mammalian signal transductionCellular communication is vital for processes like cell division, movement, stasis and programmeddeath. The information used in these processes needs to be transmitted across the cell membrane to thenucleus. This transmission of information is referred to as signal transduction. Studying this is importantbecause cancer cells have major problems with their signalling networks.

Ras genes encode small (21kD) guanine nucleotide binding proteins that operate as molecular switches insignal transduction pathways downstream of tyrosine kinase and G-protein coupled receptors. Ras isactivated by guanine nucleotide exchange factors that catalyse exchange of GTP for GDP. The binding ofGTP to Ras induces a conformational change that allows RasGTP to activate multiple effector pathways.

Some 25% of human tumours have point mutations in one of their Ras genes which render the GTPaseactivity of the mutant protein resistant to GAP stimulation. Oncogenic Ras is therefore fixed in the activatedGTP bound state and constitutively activates its effector pathways. These include: the Raf/MEK/MAPkinase cascade, phosphatidylinositol-3-kinase (PI3K) and networks of other Ras-related proteins includingRal, Rac, Rho, and Cdc42. The consequences of these events is stimulation of cell proliferation.

In order to function Ras proteins must be localized to the inner surface of the plasma membrane. This isachieved by the addition of a C-terminal membrane anchor in the endoplasmic reticulum. From there Rasproteins must be trafficked to discrete regions or microdomains of the plasma membrane. How Ras proteinstraffic to these domains and how Ras function is regulated by membrane interactions is a major focus ofour work. This has major relevance in the design of new anti-cancer therapeutics.



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Tumours are different enough from the person in which they grow that the body’s defences againstinfection can recognise them as foreign, but unlike infections, tumours are poorly controlled by thesedefences. There are many reasons for this - some relate to the body’s natural reluctance to attack itself,and this problem can be overcome through better vaccines. Our work focuses on understanding howthe body chooses not to attack tumour cells, and on developing vaccines to reverse this reluctance.

Targeting immunotherapy to epithelial tumoursWe use a model in which mice are transplanted with skin transgenic for the E7 protein of HPV16 to mimicthe immunobiology of presentation of self antigen by tumours and normal tissue in the periphery. Weobserve that E7 transgenic skin is not rejected by immunocompetent animals even if immunised with E7protein and adjuvant. However treatment of grafted animals with Listeria results in prompt graft rejectionand acquisition of memory immune responses sufficient to allow subsequent rejection of further E7transgenic grafts without further Listeria exposure. We are currently exploring the molecular and cellularmechanisms of self tolerance and of rejection using this model and developing surrogate markers for aneffective immune response that could be applied to our clinical trials of E7 specific immunotherapy forcervical premalignancy. This work is being undertaken in collaboration with Dr Ranjeny Thomas’ dendriticcell biology laboratory at CICR and Dr David Hume’s macrophage biology centre at IMB.

Codon usage as a determinant of expression of papillomavirus genesMany viruses including papillomaviruses utilise codons which are rarely used in mammalian genes. Wehave shown that papillomavirus capsid proteins are poorly expressed in undifferentiated epithelial cellsbut well expressed in their differentiated progeny, and that the block to expression in undifferentiated cellsis overcome by modifying codon usage to the mammalian consensus. Current work is therefore addressingmismatches between codon usage and AA.

Ian Frazer: Immunoregulation

Bryan Mowry: Molecular genetics of schizophreniaSchizophrenia is a brain disease characterised by psychotic symptoms such as hallucinations, delusionalideas, disordered speech and thinking, as well as deficits in emotional and social behavior. It is nowgenerally accepted that schizophrenia is a brain disease with a predominantly genetic basis. Our work isaimed at identifying genes for this devastating disease that afflicts an estimated 1% of the world population.

While the causes of schizophrenia remain unknown, evidence from family, twin and adoption studiesclearly demonstrates that it aggregates in families, with this clustering largely attributable to genetic ratherthan cultural or environmental factors. However, epidemiological data and molecular genetic studiesdemonstrate that susceptibility to schizophrenia is not the result of a mutation to a single major gene.Rather, it is likely that there is a number of interacting genes of small to moderate effect that interact witheach other and with non-genetic risk factors to confer schizophrenia susceptibility.

Current candidate-gene and genome-wide linkage studies provide some evidence for the involvement of anumber of specific genes (e.g. serotonin 5HT2a receptor gene and the dopamine D3 receptor gene) and asyet unidentified factors localised to specific chromosomal regions including 2q, 6p, 6q, 8p, 13q and 22q.These data provide suggestive, but no conclusive evidence for causative genes. Our work is aimed atidentifying these genes. In collaboration with national and international colleagues, we are studying bothethnically diverse (heterogeneous) and genetically isolated (homogeneous) populations, to account fortwo different possibilities:

• The same, frequently occurring causative genes occur in all populations.

• Rare genes may exist in one or more genetically homogeneous populations.

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The aim of this project over the next three years is to establish a world class, human genetics initiativeinvolving close collaboration between the Institute for Molecular Bioscience and the Pakistan geneticscommunity. This will involve the collaboration of a network of clinicians and researchers in Pakistanwho will ascertain and collect large inbred pedigrees with human genetic diseases, suitable for genemapping studies. In Australia, the genotyping and mutation detection studies will be undertaken and anumber of Pakistani students will be trained at the IMB .

We predict that Pakistan is one of the best populations for large scale gene-mapping studies, because of itsvery high birth rate and high proportion of consanguineous marriages. Pakistan has one of the fastestgrowing populations in the world, increasing by about one million people every 12 weeks. The largeaverage sib-ship size coupled with a high frequency of marriages between close relatives within largeextended clans greatly facilitates the mapping of many disease genes.

In a pilot study conducted at the IMB during 2000, we ascertained pedigrees with various genetic disorderssuitable for gene mapping studies. These disorders included diabetes, schizophrenia, mental retardation,epilepsy, depression, bipolar disorder, blindness, deafness, various skin disorders, cranio-facial and skeletalabnormalities.

We currently have a project underway to map schizophrenia genes. Several of these families have 20 ormore affected individuals, representing some of the largest schizophrenia families identified to date. Theanalysis of such families may complement other approaches – such as sib pair studies in heterogeneouspopulation. Indeed if large families with multiple affected individuals are useful in the search for thegenetic determinants of complex disorders, then Pakistan is clearly an ideal source.

Michael Denton and Jane Olsson: Human genetics project

Michael R. James: Genetic epidemiologyProfessor James’ research interests are in the fields of genomics and genetics of complex diseases inhumans and model organisms, and applying gene therapy and functional genomics to treat these diseases.In addition he has an interest in large-capacity vectors for gene therapy and functional genomics. Hiswork involves the complex disease projects in the Genetic Epidemiology Unit, and the SNP genotypingfacility at QIMR, which will become a new node of the Australian Genome Research Facility.

The genetic epidemiology of traits affecting common diseases has major impacts on the health of Australiancommunities including alcohol and nicotine dependence, anxiety and depression, asthma, cardiovascularrisk factors, endometriosis, fertility and melanoma. In addition to establishing a laboratory for moleculargenetics within the Genetic Epidemiology group at QIMR, Professor James is responsible for implementingthe SNP typing program in collaboration with the Australian Genome Research Facility.

In 1994 he constructed the first whole-chromosome Radiation Hybrid (RH) map. This was the first large-scale integrated physical and genetic map complete with respect to a chromosome, and the first tosystematically map ESTs. The map of chromosome 11 coincided with an urgent need to exploit huge geneand EST databases and in 1995 led to the formation of a world consortium to undertake a similar projectfor the whole rat genome. This Gene Map of 16,000 genes and ESTs pioneered the Positional Candidateapproach to disease genes discovery and lead to a landmark high resolution comparative map (mouse/rat/human) based on fully integrated RH maps for the rat.

Professor James’s interests also include using large genomic DNA for gene therapy and functional genomics.The delivery of genomic DNA enables genes to be transferred as complete loci and include regulatorysequences, introns and native promoter elements, increasing the likelihood of sustained physiologicallevels of expression in an appropriate tissue-specific and developmentally programmed manner.



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Molecular archaeology is a relatively recent expansion of archaeological science into the analysis ofancient proteins and DNA as applied to both plant and animal artefact, use residues and skeletal remains.The aim of our research is to provide an extra dimension to the traditional approaches used to reconstructpast cultures. Our areas of interest lie in the preservation of biomolecules, species identification, populationgenetics, identification and evolution of diseases in the past, and primate/ human evolution.

Past research emphasis lay in understanding the processes involved in the preservation of biomolecules,and from that knowledge devising efficient, relatively non-destructive, methods for extraction, purificationand amplification of ancient DNA. At present the oldest confirmed blood residues on stone artifacts areabout 2 million years old, from the Sterkfontein Cave site in South Africa. We have optimised our methodsto permit PCR amplification from as little as 300 micrograms of bone powder and 50 microliters ofaqueous extract from stone tool surfaces. Species identification using the 28S rRNA gene, and sexing ofhuman skeletal remains is now routine. Evolutionary studies of both human and animals, especially extinctmegafauna and primates, using genomic DNA and human endogenous retroviruses are ongoing.

In the past year our emphasis shifted to the detection and analysis of human diseases in the past. Two studieswere undertaken using mummified tissue from Hungary and Israel,and bone samples from the Musuem of London. Many diseasesleave traces of their presence as alterations of bone including pitting,remodelling, and resorbtion. Unfortunately many different andunrelated diseases can leave similar effects. The general state ofhealth of ancient communities can tell us about living conditionsand differential mortality rates as cultures developed from huntersto farmers, and later to city dwellers. We focussed on Yersinia pestis,the causative agent of black plague because the terminal stages ofthe disease result in large numbers of the bacteria being preservedin bone. We targeted the YP1 and 2 regions of the pla gene in Ypestis and were successful using bone dating to the 1347-1350 ADepidemic in London. In another study Mycobacterium tuberculosiswas targeted specifically to investigate any change through time ofof the insertion sequence IS6110, and the S12 gene, using boneand mummified tissue spanning the last 5000 years. Sequencevariation in the past, compared with modern M. tuberculosis, showsthat IS6110 sequence has changed while the S12 gene sequencehas not changed over time. We are now looking to rapidly screenfor bacterial and retroviral diseases in all skeletal remains that comethrough the lab.

Finally, we are working on a project that will ultimately repair damaged ancient DNA. A major milestonewas reached with the development of a method to damage plasmid DNA in a way that mimics the damagepattern of ancient DNA extracted from 60-100 thousand year old bone and tissue. Our goal is to repairoxidative and other damage to permit PCR amplification ofup to 1 kb fragments. This project has important implicationsfor retrospective forensic DNA cases.

Thomas H. Loy: Molecular archaeology

One of the most dense clusters of redblood cells ever recorded. Generallyonly a few isolated red cells manageto survive the drastic chemicalchanges that occur as blood dries.Sterkfontein Cave, member 5, ca. 2million years old.

Dragging of wet blood across the surface of a stone artifactindicates how the tool was held and in what orientation itwas used during butchery. Wet blood smears indicate thatfresh meat was being butchered, and not scavenged from aprevious predator kill. Sterkfontein Cave, member 5, ca.2 million years old.

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Joint Ventures



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The Australian Genome Research Facility,established by the Federal Government as a MajorNational Research Facility in 1997 has now beenin operation for four full financial years.

At the four year point, the AGRF consists of twofully functioning laboratories at The Universityof Queensland in Brisbane and at the Walter ElizaHall Institute in Melbourne, with expert staff anddedicated equipment that provide large scale DNAsequencing, genotyping and microarrayproduction to research groups and industrialorganisations throughout Australia as well as inthe international arena.

In the 2000/2001 financial year, the AGRFconducted over 200,000 DNA sequencing analyses(generating over 100 Mb of raw DNA sequenceinformation) from a wide variety of organismsincluding bacteria, plants, animals and humans.

AGRF also carried out over 1.3 million genotypinganalyses for gene mapping, primarily in humans,but also in other animal and plant species.

Australian Genome Research Facility

The AGRF has been fortunate to secure a newround of funding from the MNRF Program, $14million over the next five years. This funding willbe used to upgrade its equipment base and toexpand its services into SNP genotyping, inconjunction with the Queensland Institute ofMedical Research, and into agricultural genomics,in conjunction with the Waite Institute and theSouth Australian Agricultural Research Institute(SARDI) in Adelaide.

With these resources and new partnerships, wehope also to continue and expand our policy ofsupporting the development of key projects ofscientific and practical importance, and to placeAustralia at the forefront of genomic discoveryinternationally.

What is now needed is a framework for providingthe substantive resources to enable Australianresearch organisations to take advantage of theinfrastructure provided through AGRF and totackle significant genomics projects ofinternational importance.

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The ARC Special Research Centre for Functionaland Applied Genomics (SRC) was established in2000. The aim of the SRC is to provide anddevelop, limiting technologies that can expeditethe identification, characterisation and utilisationof genomic information.

In the first year of operation, most of the keyappointments of professional officers werecompleted and management procedures wereestablished to ensure that the core technology unitsoperate efficiently.

The core units are:1 Computational Biology;2 Microarrays;3 Transgenic Animal Service Queensland

(TASQ); Protein Expression Facility;4 Molecular Interactions Unit;5 Structural Biology Unit;6 Proteomics and Mass Spectroscopy Unit;

and7 Medicinal Chemistry Unit.

To ensure optimal use of the infrastructure andexpertise developed within the SRC, each of theUnits offers services and materials to externalclients on a full-cost-recovery basis. In 2001, suchservices have been used by university, researchinstitute and industry clients from Australia andoverseas.

Most of the research in the IMB utilises theinfrastructure of the SRC, and scientific highlightsare reported separately in this report.

A major highlight in development of infrastructurewas the commissioning of the high capacityarrayer for production of cDNA microarrays, andproduction of quality microarrays from mousecDNAs.

ARC Special Research Centre for Functional and Applied Genomics

In late 2001, the Microarray Facility purchasedthe first set of human 70mer oligonucleotidesfrom Compugen to meet the massive demand forquality human cDNA microarrays.

The facility also produces custom arrays for arange of customers working on everything frompineapples to cattle.

TASQ expanded the scope of its activities fromthe production of transgenic mice to includegenotyping of progeny, embryo freezing andrederivation and other services essential to mouse-based research.

Major advances in protein structure and functionanalysis arise from doubling of X-raycrystallography capacity and establishment ofhigh-throughput crystallisation infrastructure,expanded capacity for studies of molecularinteractions using the new BiaCore3000instrument, and commissioning of protein-chiptechnology in the form of the Ciphergen SELDI-TOF instrument.



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The Queensland node makes upapproximately 40% of the CRC activity.

The focus is therapeutic target geneidentification and validation.

In essence, we seek to expand our knowledge ofthe ways that macrophage function is regulated.

We want to identify genes that are regulated inmacrophages in inflammatory disease processes,and determine which of those genes is absolutelyrequired for disease progression.

We seek to develop ways of screening for potentialtherapies that interfere with the function of thatgene target.

Professor Hume is also Director of Education inthe CRC.

The CRC offers graduate students a uniqueenvironment in which to appreciate the industryapproaches to research and development.

The partnership with AZ provides an opportunityto gain experience within a major drug company.

The CRC for Chronic Inflammatory Diseases wasawarded in 2001 with a $2.3M per annum grantfrom the Federal Government. It commencedoperations in September under the direction ofProf. John Hamilton (CEO).

One of the three major nodes is at the IMB basedin the laboratory of Professor David Hume.

Other nodes are the University of Melbourne(Prof. Hamilton, Assoc. Prof. Gary Anderson &Dr Glen Scholz) and Monash University (Prof.Paul Hertzog).

The major pharmaceutical company, Astra-Zeneca(AZ), is the industry partner.

The CRC activities are focussed on two diseasesthat together contribute to a massive communityburden, rheumatoid arthritis and chronicobstructive pulmonary disease (COPD).

The research activities of the CRC are focussedon developing innovative therapies for thesechronic inflammatory diseases throughunderstanding the basic biology of macrophages.

These cells of the innate immune system areessential for the initiation of inflammatory diseaseprocesses, and their products contribute directlyto the tissue destruction that causes loss of functionand chronic pain.

Cooperative Research Centre for Chronic Inflammatory Diseases

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The IMB is a core participant in the CooperativeResearch Centre for Discovery of Genes forCommon Human Diseases (Gene CRC).

The IMB’s Professor Brandon Wainwright isDeputy Director of the Gene CRC and Chair ofthe Gene CRC’s Scientific Advisory Group.

Established in 1997, the Gene CRC has developedan exciting and highly competitive researchportfolio that is complemented by an extensiveeducation and ethics program, and brings togetherAustralia’s leading genetics research groups.

The IMB is joined by QIMR, Walter and ElizaHall Institute of Medical Research, MurdochChildrens Research Institute, and, as an associatemember, The Menzies Centre for PopulationHealth Research in Hobart. Cerylid Biosciencesin Melbourne, is the administrative centre andcommercial partner of the Gene CRC.

A major objective of the Gene CRC is to identifyand study genes that are important in determiningsusceptibility to common human diseases.

The basal cell carcinoma research conducted atthe IMB by Professor Brandon Wainwright andDr Carol Wicking contributes to the Gene CRC’simpressive project portfolio.

Cooperative Research Centre for the Discovery of Genes for CommonHuman Diseases

The Gene CRC is committed to empowering andengaging the Australian community for aninformed debate on the applications of humangenetic technology.

To this end, an education and ethics program,geneEDUCATION, has been developed.

This program seeks to provide knowledge andskills related to human genetic research to a widerange of people in the community, includingprimary and secondary students and their teachers,health professionals, financiers and the generalpublic.

Angela Wallace, based in the IMB’s Marketingand Communications Unit, is jointly appointedwith the IMB and the Gene CRC to assist withthe planning and implementation of the educationand ethics program.

Highlights of geneEDUCATION in 2001 include:

• genETHICS Competition for secondarystudents

• Undergraduate Research OpportunityProgram (UROP)

• Gene CRC web site - www.genecrc.org.



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Albion Fisheries, Mauritius.

Analytica Therapeutics Inc, SanFrancisco, USA.

Australian National University, Canberra.

Austrian Academy of Science, Austria.

AVRAM, Reunion Is, France.

Baylor College of Medicine, USA.

Brain Science Institute, Riken, Japan.

Bringham Young University, Salt Lake City, USA.

Cambridge University, UK.

Case Western Reserve University, Ohio, USA.

Childrens Medical Research Institute, Sydney, AUST.

CNRS, Lyon, France.

Colorado State University, USA.

Cornell University, New York, USA.

CSIRO, AUST.

Cytopia, Melbourne, AUST.

Dalhousie University, Canada.

Deakin University, Melbourne, AUST.

Duke University , USA.

Duke University Medical Centre, USA.

Edison Institute, Ohio, USA.

Emory University, USA.

Eppley Cancer Institute, Nebraska, USA.

ETH, Switzerland USA.

European Molecular Biology Laboratory, Heidelberg, Germany.

Flinders University Medical Centre, Adelaide, AUST.

Fox Chase Cancer Center, Philadelphia, USA.

Garvan Institute of Medical Research, Sydney, AUST.

Glaxo Wellcome, USA.

Glaxo Wellcome, Stevenage, UK.

Griffith University; Brisbane, AUST.

Hagedorn Institute, Denmark.

Harvard Medical School, Boston, USA.

CollaborationsVital to the world-leading research at the IMB are collaborations with other institutions, both internationally and nationally, that enablemutually beneficial synergies and exchanges and further develop the IMB’s scientific standing. These collaborations are with manyglobally recognised research institutions with over 130 international projects and a further 140 nationally. In 2001, our partners included:

Heinrich-Heine University, Dusseldorf, Germany.

Hong Kong University, Hong Kong.

Hopital de Beaumont, Lausanne, Switzerland.

Howard Florey Institute, Melbourne, AUST.

Illinois Natural History Survey.

IMP, Vienna.

Institut de Génétique et Biologie Moléculaire et Cellulaire, France.

James Cook University, Townsville, AUST.

John Curtin School of Medical Research, Canberra, AUST.

Kolling Institute of Medical Research, Sydney, AUST.

LaTrobe University, Melbourne, AUST.

Ludwig Institute for Cancer Research, Melbourne, AUST.

Massachusetts General Hospital, USA.

McArdle Institute for Cancer Research, Madison, Wisconsin USA.

Medical Research Council, Mammalian Genetics Unit, Harwell, U K.

Merck Laboratories, Philadelphia, USA.

Mimetopes, Melbourne, AUST.

Monash University.Melbourne, AUST.

MRC National Institute for Medical Research, U K.

National Cancer Institute, Frederick, USA.

National Institute of Chemistry.Ljubljana, Slovenia.

National Institutes of Health, Bethesda, USA.

Natural History Museum, London.

NeuroGadgets Inc, Canada.

NHGRI NIH.Bethesda, USA.

Northwestern University Medical School, Chicago, USA.

NovoNordisk , Copenhagen, Denmark.

Osaka Biosciences Institute, Japan.

Osaka University, Japan.

Oxford University, U K.

Peter MacCallum Cancer Institute, Melbourne, AUST.

Pharmaquest Ltd, Brisbane, AUST.

Picower Medical Research Institute, Manhassat, USA



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Princess Alexandra Hospital, Brisbane, AUST.

Queensland Clinical Genetics Service, Brisbane, AUST.

Queensland Institute of Medical Research, Brisbane, AUST.

Queensland Museum, Brisbane, AUST.

Queensland University of Technology, Brisbane, AUST.

RMIT University, Melbourne, AUST.

Samuel Lunenfeld Research Institute, Canada.

San Diego Zoological Society, USA.

Scripp’s University , San Diego, USA.

Sheffield University, UK.

Sir Albert Sakzewski Virus Research Centre, Brisbane, AUST.

St Vincent’s Institute of Medical Research, Melbourne, AUST.

Sydney University, Sydney, AUST.

Terrace Eye Centre, Brisbane, AUST.

The New Children’s Hospital, Sydney, AUST.

Tokyo Medical and Dental University, Japan.

Tokyo University, Japan.

Trieste, Italy.

University College, London, U, K.

University Hospital Nijmegen, The Netherlands.

University of Adelaide, AUST.

University of Arizona, Tucson, USA.

University of Caen, France.

University of Calgary, Canada.

University of California, San Diego, USA.

University of Copenhagen, Denmark.

University of Edinburgh, UK.

University of Geneva, Switzerland.

University of Glasgow, UK.

University of Helsinki, Finland.

University of Jyvaskala, Finland.

University of Kalmar, Sweden.

University of Kansas, Lawrence, USA.

University of Kuwait.

University of Manchester, UK.

University of Melbourne, Melbourne, AUST.

University of Michigan, Ann Arbor, USA.

University of Montreal, Canada.

University of Munich, Germany.

University of New South Wales, Sydney, AUST.

University of Newcastle, Newcastle, AUST.

University of Oregon, USA.

University of Ottawa, Canada.

University of Oulu, Finland.

University of Pittsburgh, Pennsylvania, USA.

University of Queensland, Brisbane, AUST.

University of Queensland Medical School, Brisbane, AUST.

University of Southern Queensland, Toowoomba, AUST.

University of Technology, Sydney, AUST.

University of Texas, Austin, USA.

University of the Witwatersrand, Johannesburg, South Africa.

University of Tullane, New Orleans, USA.

University of Utah, USA.

University of Utrecht, The Netherlands.

University of Wales, College of Medicine, Cardiff, UK.

University of Western Australia, Perth, AUST.

University of Wisconsin, USA.

University of York, UK.

VA Hospital Boston, USA.

Vanderbilt University, Nashville, USA.

Victorian Infectious Diseases Reference Lab , Melboourne, AUST.

Walter and Eliza Hall Institute, Melbourne.

Washington University, St Louis, USA.

Washington University School of Medicine, USA.

Wistar Institute, Philadelphia, USA.

X-ceptor Therapeutics Inc., San Diego, USA.

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In 2001, IMBcom continued to initiate regular meetings with research groups within the IMB toidentify projects that have the potential to lead to spin-offs, alliances or licensing opportunitieswith industry partners.

One outcome of this initiative was the establishment of a small internal development grantscheme for selected projects. The aim of the development grants was to fund proof of principlestudies managed in partnership with IMBcom. The three seed development grants supportedin 2001 were: Crim1 - Melissa Little; Sox18 – Peter Koopman and George Muscat; andCCK insecticidal proteins- David Craik. The projects were successful in nurturingrelationships and stimulating applied outcomes from projects that were at too early a

stage to attract pre-seed funds such as UniSeed and BioStart.

Four new spin-out companies were also established this year:

Protagonist Pty Ltd (formerly Cytokine Mimetics)Protagonist was established to apply a novel generic technology for the development ofmolecules that inhibit or mimic protein/protein interactions such as those involving cytokines.The technology enables the sculpting of protein functions onto new frameworks that haveimproved bioavailability characteristics when compared to the native protein. This processhas the potential to revolutionise the treatment of many important diseases. First roundventure capital of $3m has been invested by Start-Up Australia and Dr Mark Smythe hastaken up appointment (50% time) as interim CEO. Other positions (primarily scientific)have been advertised. An application for a Biotechnology Innovation Fund grant wassuccessful in attracting the maximum award of $250,000.

Nanomics Biosystems Pty LtdNanomics Biosystems has a variety of high throughput screening colloidal technologieswith potential applications in genomics, proteomics and combinatorial drug discovery.The core of the technology lies in the ability to cheaply produce, bar-code and individuallyaddress extremely large (> 1010) compound libraries. The initial Board and ScientificAdvisory Board were appointed, and Dr Dan Syrdal was seconded from Heller Ehrmann,USA as interim CEO (50% time). A number of potential applications are now being exploredin collaboration with IMB scientists.

Mimetica Pty LtdMimetica exploits an early stage technology opportunity involving methods for the creationof novel molecules with significant potential as new drugs. The technology uses naturalpeptides and known related compounds as models for the design of the new biologicallyactive molecules, and is potentially a highly efficient method for drug candidate generation.The recently incorporated company is in advanced negotiations with three venture capitalcompanies to secure up to $1million in funds. Mimetica Pty Ltd was successful in attractingan initial investment of $250,000 under the State Government BioStart program and anapplication for BIF Grant funding was submitted in the last round of 2001.

Kalthera Pty LtdThe cyclic cystine knot (CCK) technology stems from the discovery and exploitation of aunique class of plant derived peptides with a remarkable diversity of potential applications.These include identification of natural therapeutic peptides, the generation of insect resistantplants, the creation of stable bioavailable frameworks to carry drug epitopes and the use ofplants as hosts for the economical manufacture of protein drugs. Kalthera was awarded aBiotechnology Innovation Fund grant of $250,000 and as a result incorporated in October2001. Matching funding for this grant has currently been underwritten by IMB, but otherpotential sources of pre-seed funding are being investigated.

IMBcom Pty Ltd



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Following is a summary of the activities of three previously established spin-out companies:

Xenome LtdXenome harnessing the great variety of Australian venomous species by evaluating their venomsas potential therapeutics. Xenome Ltd was formed to exploit IMB’s competitive edge in the isolationand exploitation of toxins from marine cone snails and other venomous species. Second roundventure capital of $4.5m was raised from Biotech Capital ($3.5m) and Medica Holdings ($1.0m).Other highlights of 2001 included the award of a $1.6m AusIndustry START grant, the appointmentof Prof. Tony Evans as CEO, and the identification of a new class of analgesic agents acting on thenoradrenaline transport system.

Australian Genome Diagnostics (AGD)AGD has ceased trading, resulting in a net loss to IMBcom of $150,000 ($100,000 initial investment,$50,000 loan). A final report on the wind-up of the company is to be provided by the IMB andUniQuest representatives on the Board of the company.

Promics Pty LtdPromics creates small molecules that reproduce or mimic secondary structural characteristics ofproteins to make therapeutic compounds. The company rejected a scrip-for-scrip takeover offerfrom a US biotechnology company. Current shareholders Rothschild Bioscience and Start-UpAustralia have agreed in principle to provide an additional $4 million in second round venturecapital to fund clinical trials and pipeline expansion.

While the focus this year has been on establishing spin-out companies, IMBcom plans to focus attentionon establishing industry alliances in 2002. Several of the big pharmaceutical companies have approachedIMBcom with a view to identifying suitable projects, largely driven by the IMB’s commitment to highquality research across the spectrum from gene to drug, and the subsequent opportunity to partner withIMB to feed their drug development pipelines.

A Memorandum of Understanding has been signed between Itochu Inc. and the University of Qld (IMB).The future focus of the relationship will be on the bioinformatics area in which IMB has a growingcapability.

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Developing Excellence

DevelopingExcellence

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The Office of Public Policy and Ethics (OPPE), a new collaborative initiative between the IMB and UQ’sFaculty of Social and Behavioural Sciences, was established in September 2001 with the appointment ofProfessor Wayne Hall as Director.

The mission of OPPE is to undertake research and analysis on ethical and public policy issues raised bybiotechnology and to use the knowledge gained to enhance public discussion of, and participation in,decisions about these developments. Our commitment to this agenda is reflected in the following goals:

• To develop a framework for ethical and public policy analysis.

• To identify known and potential risks and benefits of biotechnologies.

• To contribute effectively to the public debate in this area.

• To develop methods for informed and meaningful public participation in decision and policy-making.

In pursuing our goals we have undertaken research on ethical issues in risk management and are currentlyengaged in analyses of the policy implications of cancer and behaviour genetics.

The ultimate aim of our work is to contribute to the formulation of public policy that will minimise therisks and maximise the benefits of biotechnology.

Highlights from 2001 included the appointments of Professor Wayne Hall as Director of the OPPE and ofLucy Carter as a part time Research Assistant in September; an analysis of the ethical issues in riskmanagement for World Health Organization and the United Kingdom Department of Health Consultationon Risks to Health, London, 23-24 October, 2001; and an estimation of the contribution that illicit druguse makes to the Global Burden of Disease for the World Health Organization.

In the coming year, OPPE will be expanded to employ two full time Senior Research Assistants, a Librarianand a part time Research Assistant, making up a multi-disciplinary group that includes a biological scientist,a philosopher, a psychologist, a sociologist, and alibrarian.

In 2002, OPPE is planning to:

• Development of a Strategic Plan and theidentification of research priorities.

• Analysis of the potential roles of biotechnologyin reducing the disease burden of cigarettesmoking.

• Analysis of the ethical issues raised in triallingand using cocaine vaccines to treat and preventcocaine dependence for the World HealthOrganization.

• Analysis of the ethical aspects of human andanimal neuroscience research on addiction for theWorld Health Organization.

• Analysis of the ethical issues and policyimplications of cancer genetics.

Office of Public Policy and Ethics

Prof. Wayne Hall AM,Director, Office of Public

Policy and Ethics

OPPE Mission

To undertake ethical and public policyanalyses of the known and potential risks andbenefits of biotechnology, to contributeeffectively to public debate and encourageinformed public participation in decision andpolicy-making.

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IMB Publications 2001Abbenante, G., Leung, D., Bond, T., Fairlie, D.P.(2001) An efficient Fmoc strategy for the rapidsynthesis of peptide para-nitroanilides. Letters inPeptide Science. 7:347-51

Abrami, L., Fivaz, M., Kobayashi, T., Kinoshita,T., Parton, R. G., Gisou van der Goot, F. (2001)Cross-Talk between caveolae andglycosylphosphatidylinositol-rich domains.Journal of Biological Chemistry 276: 30729-30736

Appleton, T.G., Fairlie, D.P., Hoang, H., Kelso, M.,March, D., Oliver, W. (2001) Control of peptideconformation by palladium (II) coordination.Journal of Inorganic Biochemistry 86:127

Armishaw, C. J. and Alewood, P. F. (2001) Rapidchemical protein synthesis – Meeting the futuredemands of biotechnology. Today’s Life Science 13(6): 26-32

Bartlett, S.E., Banks, G., Reynolds, A.J., Waters,M.J., Hendry, I.A., Noakes, P.G. (2001) Alterationsin ciliary nephrotic factor signalling in rapsyndeficient mice. Journal of Neurological Science64:575-81

Blanchard, H., Fontes, M. R. M., Hammet, A., Pike,B.L., Teh, T., Gleichmann, T., Gooley, P. R., Kobe,B. and Heierhorst, J. (2001) Crystallization andpreliminary X-ray diffraction studies of FHAdomains on Dun1 and Rad53 protein kinases. ActaCrystallographica D57: 459-61

Bourne, G. T., Golding, S. W., McGeary, R. P.,Jones, A., Marshall, G. R., Meutermans, W. D. F.,Alewood, P. F. and Smythe, M. L. (2001) Anevaluation and use of a novel safety catch linkerfor Boc-based assembly of cyclic peptide libraries.Journal of Organic Chemistry 23: 7706-7713

Bourne, G.T., Golding, S. W., Meutermans, W. D.F. and Smythe, M. L. (2001) Synthesis of a cyclicpeptide library based on the somatostatin sequenceusing the backbone amide linker approach. Lett.Peptide Science 7: 311-316

Bowles, J. and Koopman, P. (2001) New clues tothe puzzle of mammalian sex determination.Genome Biology 2: Reviews 1025

Box, N. F., Duffy, D. L., Chen, W., Martin, N. G.,Sturm, R. A., Hayward, N. K. (2001) MC1Rgenotype modifies risk of melanoma in familiessegregating CDKN2A mutations. AmericanJournal of Human Genetics 69: 765-773

Box, N. F., Duffy, D. L., Irving, R. E., Russell, A.,Chen, W., Griffiths, L. R., Parsons, P. G., Green,A. C. and Sturm, R. A. (2001) Melanocortin-1receptor genotype is a risk factor for basal andsquamous cell carcinoma. Journal of InvestigativeDermatology 116: 224-229

Brindley, P. J., Kalinna, B. H., Wong, J. Y. M.,Bogitsh, B. J., King, L. T., Smyth, D. J., Verity, C.K., Abbenante, G., Brinkworth, R. I., Fairlie, D.P., Smythe, M. L., Milburn, P. J., Bielfeldt-Ohman,H. and McManus, D. P. (2001) Proteolysis ofhuman hemoglobin by schistosome cathepsin D.Molecular and Biochemical Parasitology.112:171-77

Brown, D. L., Heimann, K., Lock, J., Kjer-Nielsen,van Vliet, C., Stow, J. L. and Gleeson, P. A. (2001)The GRIP domain is a specific targeting sequencefor a population of trans-golgi network derivedtubulo-vesicular carriers. Traffic 2: 336-344

Bryant, N. J. and James, D. E. (2001) Vps45pstabilises the syntaxin homologue Tlg2p andpositively regulates SNARE complex formation.EMBO Journal 20: 3380-3388

Bullejos, M. and Koopman, P. (2001) Spatiallydynamic expression of Sry in mouse genital ridges.Developmental Dynamics 221: 201-205

Bullejos, M., Bowles, J. and Koopman, P. (2001)Searching for missing pieces of the sex-determination puzzle. Journal of ExperimentalZoology 290: 517-522

Cain, S. A., Woodruff, T. M., Taylor, S. M., Fairlie,D. P. and Monk, P. N. (2001) Modulation of ligandselectivity by mutation of the first extracellularloop of the human C5a receptor. 2BiochemicalPharmacology 61: 1571-1579

Campbell, N. J. H., Sturm, R. A. and Barker, S. C.(2001) Large mitochondrial repeats multipliedduring PCR. Molecular Ecology Notes 1:336-340

Carter, R. W., Sweet, M. J., Xu, D., Klemenz, R.,Liew, F. Y. and Chan, W. (2001) Regulation ofST2L expression on T helper (Th) type 2 cells.European Journal of Immunology 31: 2979-2985

Catimel, B., Teh, T., Fontes, M. R. M., Jennings,E. G., Jans, D. A., Howlett, F. J., Nice, E. C. andKobe, B. (2001) Biophysical characterization ofinteractions involving importin- a during Nuclearimport. Journal of Biological Chemistry 276:34189-34198


77

Casarotto, M. G., Craik, D. (2001) Ring flexibilitywithin tricyclic antidepressant drugs. Journal ofPharmaceutical Sciences 90: 713-721

Chigagure, N. N., Baxter, G. D. and Barker, S. C.(2001) Microsatellite loci of the cattle tick,Boophilus microplus (Acari: Ixodidae).Experimental and Applied Acarology 24: 951-956

Chiovitti, A., Kraft, G.T., Bacic, A., Craik, D.J.,Liao, M-L. (2001) Chemistry, properties, andphylogenetic implications of the methylatedcarrageenans from red algae of the genusAreschougia (Areschougiaceae, Gigartinales,Rhodophyta). Journal of Phycology 37: 1127-1137

Craik, D., Daly, N. L. and Waine, C. (2001) Thecystine knot motif in toxins andimplications for drug design.Toxicon 39: 43-60

Craik, D. (2001) Plant cyclotides:Circular, knotted peptide toxins.Toxicon 39: 1809-1813

Darby, I. A., Bisucci, T.,Raghoenath, S., Olsson, J.,Muscat, G. E. and Koopman, P.(2001) Sox18 is transientlyexpressed during angiogenesis ingranulation tissue of skin woundswith an identical expressionpattern to Flk-1 mRNA.Laboratory Investigation 81: 937-943

Dermine, J.-F., Duclos, S., Garin, J., St-Louis, F.,Rea, S., Parton, R. G. and Desjardins, M. (2001)Flotillin-1-enriched lipid raft domains accumulateon maturing phagosomes. Journal of BiologicalChemistry 276: 18507-18512

Downes, M. and Koopman, P. (2001) SOX18 andthe transcriptional regulation of blood vesseldevelopment. Trends in Cardiovascular Medicine11: 318-324

Dressel, U., Bailey, P. J., Wang S-C, M., Downes,M., Evans, R. M., Muscat, G. E. O. (2001) Adynamic role for HDAC7 in MEF2-mediatedmuscle differentiation. Journal of BiologicalChemistry 276: 17007-17013

Dutton, J. L. and Craik, D. (2001) alpha-Conotoxins: Nicotinic acetylcholine receptorantagonists as pharmacological tools and potentialdrug leads. Current Medicinal Chemistry 8 (4):327-344

Edeling, M. A., Guddat, L. W., Fabianek, R. A.,Halliday, J. A., Jones, A., Thony-Meyer, L. andMartin, J. L. (2001) Crystallization and preliminarydiffraction studies of native and selenomethionineCcmG (CycY, DsbeE). Acta CrystallographicaSection D: 1293-1295

Evans, T., Poh, A., Webb, C., Glass, I., Carey, W.F.,Fietz, M., Wainwright, B.J., Wicking, C. (2001)Novel mutation in the delta7-dehydrocholesterolreductase gene in Australian patient with Smith-Lemli-Opitz syndrome. American Journal ofMedicinal Genetics 103:344-347

Felizmenio-Quimio, M. E., Daly, N. L. and Craik,D. (2001) Circular proteins in plants: Solutionstructure of a novel macrocyclic trypsin inhibitor

from momordica. Journal ofBiological Chemistry 276: 22875-22882

Fenner, P. and Lewis, R. (2001)in Channelopathies of theNervous System: (Rose, M. G., RC, ed.), pp. 295-307, ButterworthHeinemann.

Fletcher, B. H., Cassady, A. I.,Summers, K. M. and Cavanagh,A. C. (2001) The murinechaperonin 10 gene familycontains an intronless, putativegene for early pregnancy factor,

Cpn1rs1. Mammalian Genome 12: 133-140

Fry, B. G., Wickramaratna, J. C., Jones, A.,Alewood, P. F. and Hodgson, W. (2001) Speciesand regional variatioons in the effectiveness ofantivenom against the in vitro neurotoxicity ofDeath Adder (Acanthophis) venoms. Toxicologyand Applied Pharmacology 174: 140-148

Georgas, K., Bowles, J., Yamada, T., Koopman, P.and Little, M. H. (2001) Characterisation of Crim1expression in the developing mouse urogenital tractreveals a sexually dimorphic gonadal expressionpattern. Developmental Dynamics 219: 582-587

Gresshof, P.M., Men, A.E., Maguire, T., Carroll,B., Grimmond, S., Loha, H., Ayanru, S., Meksem,K., Lightfoot, D., Stiller, J. (2001) An integratedfunctional genomics and genetics approach todefine the plant’s function in symbiotic nodulationand nitrogen fixation of legumes. MolecularBreeding of Forage Crops. Ed G. Spangenberg. 17:275-84. Kluwer Academic Publishing, Boston.

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Grimmond, S. and Greenfield, A., (2001) cDNAmicroarrays: a user’s perspective. Expressionmeasurement by DNA array methods. Ed. B.Jordan Chapter 2: 15-33. Springer Verlag Press,New York.

Grimmond, S., Larder, R., Van Hateren, N.,Siggers, P., Morse, S., Hacker, T., Arkell, R.,Greenfield, A. (2001) Expression of novelmammalian epidermal growth factor-related gene(SCUBE2) during mouse neural development.Mechanisms of Development 102 (1-2): 209-11

Halliday, J. A. W., Franks, A. H., Ramsdale, T. E.,Martin, R. and Palant, E. (2001) A rapid, semi-automated method for detection of Gal b1-eGIcNAc a 2, 6-sialyltransferase (EC 2.4.99.1)activity using the lectin Sambucus nigraagglutinin. Glycobiology 11: 557-564

Heffernan, M.A., Thorburn, A.W., Fam, B.,Summers, R., Conway-Campbell, B., Waters,M.J., Ng, F.M. (2001) Increase of fat oxidationand weight loss in obese mice caused by chronictreatment with human growth hormone or amodified C-terminal fragment. InternationalJournal of Obesity and Related MetabolicDisorders 25: 1442-9

Himes, R., Tagoh, H., Goonetilleke, N., Sasmono,R.T., Oceandy, D., Clark, R., Bonifer, C., Hume,D.A. (2001) A highly conserved intronic elementin the c-fms (CSF-1 receptor) gene controlsmacrophage-specific and regulated expression.Journal of Leukocyte Biology 70: 812-820

Hosking, B. M., Wyeth, J. R., Pennisi, D. J., Wang,S. C., Koopman, P. and Muscat, G. E. O. (2001)Cloning and functional analysis of the Sry-relatedHMG box gene Sox18. Gene 262: 239-247

Hosking, B. M., Wang, S. C., Chen, S. L., Penning,S., Koopman, P. and Muscat, G. E. (2001) SOX18directly interacts with mef2c in endothelial cells.Biochemical and Biophysical ResearchCommunications 287: 493-500

Hume, D. A., Underhill, D. M., Sweet, M. J.,Ozinsky, A. O., Liew,F. Y. and Aderem, A. (2001)Macrophages exposed continuously tolipopolysaccharide and other agonists that act viatoll-like receptors exhibit a sustained and additiveactivation state. BMC Immunology 2: 11

Hung, B., Wang, X-Q., Cam, G.R., Rothnagel,J.A. (2001) Characterisation of mouse Frizzled-3expression in hair follicle development andidentification of the human homolog inkeratinocytes. Journal of InvestigativeDermatology 116:940-946

Im, H.J., Smirnov, D., Yuhi, T., Raghavan, S.,Olsson, J. E., Muscat, G. E., Koopman, P. and Loh,H. H. (2001) Transcription modulation of mousemu-opioid recepton distal promoter activity bysox18. Molecular Pharmacology 59: 1486-1496

Jaumont, M., and Hancock, J. (2001) Proteinphosphatases 1 and 2A promote Raf-1 activationby regulation 14-3-3 interactions. Oncogene 20:3949-3958

Jennings, C., West, J., Waine, C., Craik, D. andAnderson, M. (2001) Biosynthesis and insecticidalproperties of plant cyclotides: The cyclic knottedproteins from Oldenlandia affinis. PNAS 98:10614-10619

Jennings, I. G., Trazel, T. and Kobe, B. (2001)Essential role of the N-terminal autoregulatorysequence in the regulation of phenylalaninehydroxylase. FEBS Letters. 488: 196-200

Kennedy, D., French, J., Guitard, E., Ru, K.,Tocque, B. and Mattick, J. S. (2001)Characterisation of G3BPs: tissue specificexpression, chromosomal localisation andrasGAP120 binding studies. Journal of CellularBiochemistry 84: 173-187

Kobe, B. (2001) Crystallisation and crystalstructure determination if ribonuclease A-ribonuclease inhibitor protein complex. Methodsof Molecular Biology 160: 201-11

Kobe, B. and Kajava, A. V. (2001) The leucine-rich repeat as a protein recognition motif. CurrentOpinion in Structural Biology 11: 725-732

Kolle, S., Stojkovic, M., Prelle, K., Waters, M.,Wolf, E., Sinowatz, F. (2001) GH/GH receptorexpression and GH-mediated effects during earlybovine embryogenesis. Biology of Reproduction64:1826-34


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Koopman, P. (2001) in Genes and Mechanisms inVertebrate Sex Determination: (Scherer, G. andSchmid, M., eds.), pp. 25-56, Birkhäuser, Basel

Koopman, P., Bullejos, M. and Bowles, J. (2001)Regulation of male sexual development by Sryand Sox9. Journal of Experimental Zoology 290:463-474

Koopman, P. (2001) In situ hybridisation: fromblack art to guiding light. International Journalof Developmental Biology 45: 619-622

Koopman, P. (2001) SRY and DNA bendingproteins in Encyclopedia of Life Sciences. NaturePublishing Group. www.els.net

Koopman, P. (2001) Gonad development: signalsfor sex. Current Biology 11: R481-483

Koopman, P. (2001) The genetics and biology ofvertebrate sex determination. Cell 105: 843-847

Koopman, P. (2001) Molecular analysis of themammalian sex-determining pathway. Journal ofEndocrinology 48: 735

Korsinczky, M. L. J., Schirra, H. J., Rosengren,K. J., West, J., Condie, B. A., Otvos, L., Anderson,M. A. and Craik, D. (2001) Solution structuresby 1H NMR of the novel cyclic trypsin inhibitorSFTI-1 from sunflower seeds and an acyclicpermutant. Journal of Molecular Biology 311:579-591

Kovacs, E. M., Ali, R. G., McCormack, A. J. andYap, A. S. (2001) B-cadherin homophilic ligationdirectly signals through Rac andphosphatidylinositol 3-kinase to regulate adhesivecontacts. Journal of Biological Chemistry 277:6708-6718

Kovacs, E. M., Goodwin, M., Ali, R. G., Paterson,A. D. and Yap, A. S. (2001) Cadherin-directedactin assembly: E-cadherin physically associateswith the Arp2/3 complex to direct actin assemblyin nascent adhesive contacts. Current Biology 12:1-20

La Fontaine, S., Theophilos, M. B., Firth, S. D.,Gould, R., Parton, R. G., Mercer, J. F. B. (2001)Effect of the toxic milk mutation (tx) on thefunction and intracellular localization of Wnd, themurine homologue of the wilson copper ATPase.Human Molecular Genetics 10: 361-370

Lester, R.J.A., Thompson, C., Moss, H., Barker,S.C. (2001) Movement and stock strucutre ofnarrow- barred Spanish mackerel as indicated byparasites. J. Fish Biol. 59:833-42

Leung, D., Schroder, K., White, H., Fang, N.-X.,Stoermer, M.J., Abbenante, J., Martin, J.L., Young,P., Fairlie, D.P. (2001) Activity of recombinantdengue 2 virus NS3 protease in the presence ofNS2B cofactor, small peptide substrates andinhibitors. Journal of Biological Chemistry 276:45762-771

Lewis, R. J. (2001) The changing face of ciguatera.Toxicon 39: 97-106

Li, H., Bartold, P.M., Young, W.G., Xiao, Y.,Waters, M.J. (2001) GH induces bonemorphogenetic proteins and bone related proteinin the developing rat periodontium. Journal ofBone and Mineral Research 16:1068-76

Little, M. H., Wilkinson, L., Brown, D. L., Piper,M., Yamada, T. and Stow, J. L. (2001) Dualtrafficking of Slit3 to the mitochondria and the cellsurface demonstrates a novel localisation for a Slitprotein. American Journal of Physiology 281: 486-495

Loebel, D., Yamada, T., Yap, A., Key, B., Stanley,K., (2001) Meeting report: ICDCB, 2000. CellBiology International 24:915-16

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Loffler, K. A., Bowles, J. and Koopman, P. (2001)Assessment of candidate ovarian-determininggenes. Developmental Biology 235: 181

Luchin, A., Suchting, S., Merson, T., Rosol, T.J.,Hume, D.A., Cassady, A.I., Ostrowski, M.C.(2001) Genetic and physical interactions betweenMicrophthalmia transcription factor and PU.1 arenecessary for osteoclast gene expression anddifferentiation. Journal of Biological Chemistry276: 36703-10.

McMorran, B.J., Palmer, J., Lunn, D.P., Oceandy,D., Costelloe, E., Thomas, G.R., Hume, D.A.,Wainwright, B.J. (2001) G551D cystic fibrosismice display an abnormal host response and haveimpaired clearance of Pseudomonas lunginfection. American Journal of Physiology281:L740-L747

Martin, J. L., Begun, J., McLeish, M. J., Caine, J.M. and Grunewald, G. L. (2001) Getting theadrenaline going: Crystal structure of theadrenaline-synthesizing enzyme PNMT. Structure9: 977-985

Mattick, J. and Gagen, M. J. (2001) The evolutionof controlled multitasked gene networks: the roleof introns and other noncoding RNAs in thedevelopment of complex organisms. Molecularand Biology and Evolution 18: 1611-1630

Mattick, J. S. (2001) Noncoding RNAs: thearchitects of eukaryotic complexity. EMBOReports 2: 986-991

Miranda, K. C., Khromykh, T., Christy, P., Le, T.L., Gottardi, C. J., Yap, A. S., Stow, J. L. andTeasdale, R. D. (2001) A dileucine motif targetse-cadherin to the basolateral cell surface in madin-darby canine kidney and LLC-PK1 epithelial cells.Journal of Biological Chemistry 276: 22565-22572

Miranda, L. P., Tao, T., Jones, A., Chernushevich,I., Standing, K. G., Geczy, C. L. and Alewood, P.F. (2001) Total chemical systhesis and chemotacticactivity of human S100A12 (EN-RAGE). FEBSLetters 488: 85-90

Murrell. A., Campbell, N.J.H., Barker, S.C. (2001)Recurrent gains and losses of large (84-109 bp)repeats in the RDNA internal transcribed spaver2 (ITS2) of rhipcephaline ticks. Insect MolecularBiology 10:587-96

Olsson, J. E., Kamachi, Y., Penning, S., Muscat,G. E., Kondoh, H. and Koopman, P. (2001) Sox18 expression in blood vessels and feather budsduring chicken embryogenesis. Gene 271: 151-158

Pantaleon, M., Kanai-Azuma, M., Mattick, J.S.,Kaibuchi, K., Kaye, P.L. and Wood, S.A. (2001)FAM deubiquitylating enzyme is essential forpreimplantation mouse embryo development.Mechanisms of Development 109: 151-160.

Parton, R.G., (2001) Life without caveolae.Science 293: 2405

Parton, R.G., and Hancock, J.F., (2001) Caveolinand RAS function. Methods of Enzymology333:172-183

Payne, E., Bowles, M., Don, A., Hancock, J.,McMillan, N. (2001) Human papillomavirus type6b virus like particles are able to activate the Ras-MAP kinase pathway and induce cellproliferation. Journal of Virology 75: 4150-4157

Pennisi, D. J., Bowles, J., Nagy, A., Muscat, G.and Koopman, P. (2001) Mice null for sox18 areviable and display a mild coat defect. MolecularCell Biology 20: 9331-9336

Pennisi, D. J., James, K. M., Hosking, B., Muscat,G. E. and Koopman, P. (2001) Structure, mapping,and expression of human SOX18. MammalianGenome 11: 1147-1149

Pol, A., Luetterforst, R., Lindsay, M., Heino, S.,Ikonen, E., Parton, R.G. (2001) A caveolindominant negative mutant associates with lipidbodies and induces intracellular cholesterolimbalance. Journal of Cellular Biology 152:1057-1070

Prior I. and Hancock, J. (2001)Compartmentalisation of Ras proteins. Journalof Cell Science 114:1603-08

Prior, I.A., Parton, R.G., Hancock, J.F. (2001)Which RAS rides the raft? - Reply. Nature CellBiology 3: E172

Prior, I.A., Harding, A., Yan, J., Sluimer, J.,Parton, R.G., Hancock, J.F. (2001) GTPdependent segregation of H-ras from lipid raftsis required for biological activity. Nature CellBiology 3: 368-75


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Puri, P. L., Iezzi, S., Stiegler, P., Chen, T.-T.,Schiltz, R. L. Muscat, G. E. O., Giordano, A.,Kedes, L., Wang, J. Y. J. and Sartorelli, V. (2001)Class I histone deacetylases sequentially interactwith MyoD and pRb during skeletal myogenesis.Molecular Cell 8: 885-897

Ragan, M. A. (2001) On surrogate methods fordetecting lateral gene transfer. FEMSMicrobiology Letters 201: 187-191

Ragan, M.A. (2001) Detection of lateral(horizontal) gene transfer among microbialgenomes. Current Opinions in Genetics andDevelopment 11: 620-626

Ragan,M.A. (2001) Reconciling the many facesof latral gene transfer. Response from Ragan.Trends in Microbiology 10: 4

Ragan, M.A. (2001) Arne Jensen 1926-2000(obituary). Journal of Applied Phycology 13:1-2

Rahkila, P., Takala, T.E., Parton, R.G., Metsikko,K. (2001) Protein targeting to the plasmamembrane of adult skeletal muscle fibre: anorganised mosaic of functional domains.Experimental Cell Research 267:61-72

Riken Genome Exploration Phase 2 Group andFANTOM Consortium (2001) (Hume, D.A.acknowledged as major contributor amongst 90authors). Functional annotation of a collection ofmouse full length cDNAs. Nature 409: 685-690

Rosengren, K. J., Daly, N. L., Scanlon, M. J. andCraik, D. (2001) Solution structure of BSTI: Anew trypsin inhibitor from skin secretions ofBombina bombina. Biochemistry 40: 4601-4609

Ross, R.J.M., Leung, K.C., Maamra, M., Bennett,W., Doyle, N., Waters, M.J., Ho, K.K.Y. (2001)Binding and functional studies with the GHreceptor antagonist, B2036-PEG (Pegvisomant),reveal effects of PEGylation. Journal of ClinicalEndocrinology and Metabolism 86:1716-23

Ross, B. C., Czajkowski, L., Hocking, D.,Margetts, M., Webb, E., Rothel, L., Patterson, M.,Agius, C., Camuglia, S., Reynolds, E., Littlejohn,T., Gaeta, B., Ng, A., Kuczek, E. S., Mattick, J.S., Gearing, D. and Barr, I. G. (2001) Identificationof vaccine candidate antigens from a genomicanalysis of Porphyromonas gingivalis. Vaccine 19:4135-4142

Schepers, G. and Koopman, P. (2001) Mouse Sox8located between, not within, the t-complexdeletions tw18 and th20 on chromosome 17.Cytogenetics and Cell Genetics 93: 91-93

Schirra, H. J., Scanlon, M. J., Lee, M. C. S.,Anderson, M. and Craik, D. J. (2001) The solutionstructure of C1-T1, a two-domain proteinaseinhibitor derived from a circular precursor proteinfrom Nicotiana alata. Journal of MolecularBiology 306: 69-79

Sekiya, I., Koopman, P., Tsuji, K., Mertin, S.,Harley, V., Yamada, Y., Shinomiya, K., Nifuji, A.and Noda, M. (2001) Transcriptional suppressionof Sox9 expression in chondrocytes by retinoicacid. Journal of Cellular Biochemistry Supplement36: 71-78

Sekiya, I., Koopman, P., Tsuji, K., Mertin, S.,Harley, V., Shinomiya, K., Nifuji, A. and Noda,M. (2001) Dexamethasone enhances Sox9expression in chondrocytes. Journal ofEndocrinology 169: 573-579

Sekiya, I., Tsuji, K., Koopman, P., Watanabe, H.,Yamada, Y., Shinomiya, K., Nifuji, A. and Noda,M. (2001) SOX9 enhances aggrecan genepromoter/enhancer activity and is up-regulated byretinoic acid in a cartilage-derived cell line, TC6.Journal of Biological Chemistry 275: 10738-10744

Shao, R., Campbell, N. J. H. and Barker, S. C.(2001) Numerous gene rearrangements in themitochondrial genome of the wallaby louse,Heterodoxus macropus (Phthiraptera). MolecularBiology and Evolution 18: 858-865

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Shao, R., Campbell, N., Schmidt, E., Barker, S.(2001) Increased rate of gene rearrangement inthe mitochondrial genomes of insects in threedimensional hemipteroid orders. MolecularBiology and Evolution 18: 1828-32

Shaw, M., Murrell, A. and Barker, S. C. (2001)Low intraspecific variation in the rRNA internaltranscribed spacer 2 (ITS2) of the Australianparalysis tick, Ixodes holocyclus. ParasitologyResearch 88: 247-252

Sharpe, I. A., Gehrmann, J., Loughnan, M. L.,Thomas, L., Adams, D. A., Atkins, A., Palant, E.,Craik, D. J., Adams, D. J., Alewood, P. F. andLewis, R. J. (2001) Two new classes ofconopeptides inhibit the alpha1-adrenoceptor andnoradrenaline transporter. Nature Neuroscience 4:902-907

She, Q., Singh, R. K., Confalonieri, F., Zivanovic,Y., Allard, G., Awayez, M. J., Chan-Weiher, C.C.-Y., Clausen, I. G., Curtis, B. A., De Moors, A.,Erauso, G., Fletcher, C., Gordon, P. M. K.,Heikamp-de Jong, I., Jeffries, A. C., Kozera, C.J., Medina, N., Peng, X., Thi-Ngoc, H. P., Redder,P., Schenk, M. E., Theriault, C., Tolstrup, N.,Charlebois, R. L., Doolittle, W. F., Duguet, M.,Gaasterland, T., Garrett, R. A., Ragan, M. A.,Sensen, C. W. and Van der Oost, J. (2001) Thecomplete genome of the crenarchaeon Sulfolobussolfataricus P2. PNAS 98: 7835-7840

Shen, L.C., S-C Wang, M., Hoskings, B., andMuscat, G.E.O. (2001) Sub-cellular localisationof the steriod receptor coactivators (SRC) andMEF2 in muscle and rhabdomyosarcoma cells.Molecular Endocrinology 15: 783-796

Shurety, W., Pagan, J. K., Prins, J. B. and Stow, J.L. (2001) Endocytosis of uncleaved tumornecrosis factor-a in macrophages. LaboratoryInvestigation 81: 107-117

Simpson, F., Whitehead, J. P. and James, D. E.(2001) GLUT4 - at the cross roads betweenmembrane trafficking and signal transduction.Traffic 2: 2-11

Singh, Y., Sokolenko, N., Kelso, M. J., Gahan, L.R., Abbenante, G. and Fairlie, D. P. (2001) Novel,cylindrical, conical and macrocyclic peptides fromthe cyclooligomerization of functionalizedthiazole amino acids. Journal American ChemicalSociety 123: 333-334

Smith, A. G., Box, N. F., Marks, L. H., Chen, W.,Smit, D. J., Wyeth, J. R., Huttley, G. A., Easteal,S. and Sturm, R. A. (2001) The humanmelanocortin-1 receptor locus: Analysis oftranscription unit, locus polymorphism andhaplotype evolution. Gene 281: 81-94

Sweet, M. J., Leung, B. P., Kang, D., Sogaard,M., Schulz, K. Trajkovic, V., Campbell, C. C.,Xu, D. and Liew, F. Y. (2001) A novel pathwayregulating lipopolysaccharide-induced shock byST2/T1 via inhibition of toll-like receptor 4expression. Journal of Immunology 166: 6633-6639

Strachan, A.J., Shiels, I.A., Reid, R.C., Fairlie,D.P., Taylor, S.M. (2001) Inhibition of immune-complex mediated dermal inflammation in ratsfollowing either oral or topical administration ofa small molecule C5a receptor antagonist. BritishJournal of Pharmacology 134:1778-86

Sturm, R. A., Teasdale, R. D. and Box, N. F.(2001) Human pigmentation genes: identification,structure and consequences of polymorphicvariation. Gene 277: 49-62

Tam, S.P., Lau, P., Djiane, J., Hilton, D.J., Waters,M.J. (2001) Tissue specific induction of SOCSgene expression by prolactin. Endocrinology 142:5015-5026

Teasdale, R. D., Loci, D., Houghton, F., Karlsson,L. and Gleeson, P. A. (2001) A large family ofendosome-localized proteins related to sortingnexin 1. Biochemistry Journal 358: 7-16

Trabi, M., Schirra, H. J. and Craik, D. J. (2001)Three-dimensional structure of RTD-1, a cyclicantimicrobial defensin from rhesus macagueleukocytes. Biochemistry 40: 4211-4221

Tyndall, J. D. A. and Fairlie, D. P. (2001)Macrocycles mimic the extended peptideconformation recognized by aspartic, serine,cysteine and metallo proteases. CurrentMedicinal Chemistry 8: 893-907

Wade, N., Bryant, N. J., Connolly, L. M.,Simpson, R. J., Luzio, J. P., Piper, R. C. and James,D. E. (2001) Syntaxin 7 complexes with mouseVps10p tail interactor 1b, syntaxin 6, vesicle-associated membrane protein (VAMP)8, andVAMP7 in B16 melanoma cells. Journal ofBiological Chemistry 276: 19820-19827


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Walsh, C., Hume, D., Kobe, B. and Martin, J.(2001) in Australian Biochemist 32: 13-16

Walsh, N. C., Hume, D. A. and Cassady, A. I.(2001) Multiple promoters regulate differentialexpression of murine tartrate-resistant acidphosphatase (TRAP). Journal of Bone andMineral Research 16: S379

Wang, X.-h., Connors, M., Wilson, D., Wilson,H. I., Nicholson, G. M., Smith, R., Shaw, D.,Mackay, J. P., Alewood, P. F., Christie, M. J. andKing, G. F. (2001) Discovery and structure of apotent and highly specific blocker of insectcalcium channels. Journal of BiologicalChemistry 276: 40306-40312

Wang, X-Q. and Rothnagel, J.A. (2001) Post-transcriptional regulation of the GLI1 oncogeneby the expression of alternative 5'-untranslatedregions. Journal of Biological Chemistry276:1311-1316

Whitehead, J. P., Molero, J. C., Clark, S. F.,Martin, S., Meneilly, G. and James, D. E. (2001)The role of Ca2+ in insulin-stimulated transportin 3T3-L1 cells. Journal of Biological Chemistry276: 27816-27824

Wicking, C., and McGlinn, E. (2001) The role ofhedgehog signalling in tumorigenesis. CancerLetts. 173: 1-7

Wilce, J. A., Love, S. G., Richardson, S. J.,Alewood, P. F. and Craik, D. (2001) Synthesis ofan analog of the thyroid hormone-binding proteintransthyretin via regioselective chemical ligation.Journal of Biological Chemistry 276: 25997-26003

Wiles, J. and Hallinan, J. (2001) Guest editorial -Evolutionary computation and cognitive science:Modelling evolution and evolving models. IEEETransactions on Evolutionary Computation 5: 89

Woodruff, T. M., Strachan, A. J., Sanderson, S.,Monk, P. N., Wong A. K., Fairlie, D. P. and Taylor,S. M. (2001) Species dependence for binding ofsmall molecule agonists and antagonists of theC5a receptor on polymorphonuclear leukocytes.Inflammation. 25: 171-177

Wunderlich, W., Fialka, .I., Teis, D., Alpi, A.,Pfeifer, A., Parton, R.G., Lottspeich, F., Huber,L.A. (2001) A novel 14-kilodalton protein interactswith the mitogen-activated protein kinase scaffoldMP1 on a late endosomal /lysosomalcompartment. J Cell Biol. 152: 765-76

Yap, A. S. (2001) Initiation of cell locomotility isa morphogenetic checkpoint in thyroid epitheliacells regulated by ERK and PI3-kinase signals.Cell Motility and the Cytoskeleton 49: 93-103

Yap, A. S. and Manley, S. W. (2001) Microtubuleintegrity is essential for thyroid epithelialpolarisation and follicle formation in vitro. CellMotility and the Cytoskeleton 48: 201-212

Yeo, S.-Y., Little, M. H., Yamada, T., Miyashita,T., Halloran, M. C., Kuwada, J. Y., Huh, T.-L. andOkamoto, H. (2001) Over-expression of a slithomologue impairs convergent extension of themesoderm and causes cyclopia in embryonicZebrafish. Developmental Biology 230: 1-17

Young, W.G., Li, H., Xiao, Y., Waters, M.J.,Bartold, P.M. (2001) GH stimulated dentiogenesisin Lewis dwarf rat molars. Journal of DentalResearch 80: 1742-1747

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Dr Michael LadomeryMRC Human Genetics Unit, Edinburgh, UKThe tumour suppressor gene WT1 encodes amultifunctional transcription factor involved inpre-mRNA processing.

Professor Fujio MurakamiNeuroscience Lab, Division of BiophysicalEngineering, Graduate School of EngineeringScience, Osaka University, JapanRole of the floor plate in migration ofprecerebellar neurons.

Dr John QuackenbushThe Institute for Genomic Research, Maryland,USAAnalysis of Global Patterns of Gene Expression

Dr Ruth ArkellMRC Mammalian Genetics Unit, Harwell, UKENU mutagenesis; screening for developmentalphenotypes.

Professor Heinz BonishInstitute of Pharmacology and ToxicologyUniversity of Bonn, GermanyDiscovery of 5-HT3A splice variants that influencereceptor function

Mr Julian CribbCSIRO National Awareness ProgramMutant food or brave new world?

Dr Ricky JohnstoneCancer Immunology Division, The PeterMacCallum Cancer Institute, MelbourneRegulation of caspase-activation by the multidrugresistance protein, P-glycoprotein

Dr Brad MarshHigh Resolution Structure Laboratory, Universityof Colorado, Boulder, USA3-D structural studies of the pancreatic beta cellby high resolution EM tomography.

IMB Seminars

Professor Rolf PragerSchool of Chemistry, Physics and Earth SciencesFlinders University, AdelaideThe application of new methods for the synthesisof oxazoles and thiazoles to natural product andpeptide mimetic synthesis

Professor Chris Marshall, FRSInsitutue of Cancer Research, UKInteractions between small GTPase signalingpathways in cell transformation.

Dr Ian SmithBaker Medical Research Institute, MelbourneBeta-Amino Acid Based Inhibitors ofMetalloendopeptidases: Novel MolecularTemplates for Cardiovascular Drug Design

Professor Gene MyersInformatics Research, Celera Genomics, USAWhole Genome Assembly: Tactical and StrategicImplications

Dr Paul GooleyDepartment of Biochemistry and MolecularBiology, University of MelbourneThe solution structure of a diadenosinepyrophosphatase

Dr Carina DennisSenior Editor, Nature, Washington DC, USAPublish or Perish: Perspectives of a Nature Editor

Dr Ian TaylorInstitute for Molecular Bioscience, The Universityof QueenslandThe New Building - History, Design and Features

Dr Keith MoffatBiochemistry and Molecular Biology, Universityof Chicago, USAUltra-fast Time-Resolved MacromolecularCrystallography

Dr Robert CharleboisDepartment of Biology, University of Ottawa,Canada; Founder, NeuroGadgets Inc., CanadaReconstructing bacterial genomes


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Professor Duncan WattsDepartment of Sociology, and Center forNonlinear Earth SystemsColumbia University, USAComplex Networks

Dr KumKum KhannaSignal Transduction Lab Oncology Unit,Queensland Institute of Medical ResearchATM, a central controller of cellular response toDNA damage

Dr Rhonda PerrimanInstitute for Molecular Bioscience, The Universityof QueenslandDissecting dynamic RNA-Protein interactionsduring pre-mRNA splicing.

Professor Martin PeraMonash Institute of Reproduction andDevelopment Centre For Early HumanDevelopment, Monash Medical Centre,MelbourneBiology of human pluripotent stem cells

Professor Gary HimeDepartment of Antomy and Cell Biology,University of MelbourneAnalysing oncogenes in Drosophila - functionalstudies of Cbl and Patched.

Professor Warren EwensGenomics and Bioinformatics program,University of Pennsylvania, USAStatistics in bioinformatics: BLAST andexpression arrays

Dr Jeff GormanCSIRO Health Sciences and Nutrition, Parkville,MelbourneA perspective on the Future of Proteomics

Professor Kay DaviesHuman Anatomy and Genetics, University ofOxford, UKFlies, worms and mice in the analysis of genefunction

Dr Alan MunnYeast Cell Biology Group, Institute of MolecularAgrobiology, SingaporeYeast Homologs of Human WASP and WIP HaveMultiple Roles in Endocytosis, Cell Division, andOrganisation of the Cortical Actin Cytoskeleton

Dr Sally DunwoodieChildren’s Medical Research Institute, SydneyIdentification of novel genes required for normalembryonic development.

Ms Donmienne LeungInstitute for Molecular Bioscience, The Universityof QueenslandStudies on Serine and Cysteine Proteases

Dr Joel MackayDepartment of Biochemistry, University of SydneyA finger in each pie: multifunctional zinc fingerdomains in the control of gene expression

Professor Phil BourneSupercomputer Centre, University of California,San Diego, USAData Driven Biology Beyond the Human Genome

Professor Angel LopezCytokine Receptor laboratory, Hanson Centre forCancer Research, AdelaideA novel signalling pathway utilized by cytokinereceptors

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Dr Craig HuttonDepartment of Chemistry, University of SydneyDesign and Synthesis of Inhibitors of Enzymes inthe Lysine Biosynthetic Pathway

Dr Dagmar WilhelmResearch Centre, Karlsruhe, Institute ofToxicology and Genetics, GermanyMolecular and cellular roles of the Wilms’ tumoursuppressor WT1 in gonad development

Dr Edith GardinerBone and Mineral Research Program, GarvanInstitute of Medical Research, SydneyElevated Osteoblastic Vitamin D Receptor in Mice— Beneficial Effects on Bone Formation andResorption

Professor W van GunsterenLaboratory of Physical Chemistry, Swiss FederalInstitute of Technology, SwitzerlandThe Key to Solving the Protein Folding ProblemLies in an Accurate Description of the DenaturedState

Dr Pam SilverDana Farber Cancer Institute, Harvard University,USAGenome-wide mapping of nuclear organization

Dr Adam GodzikBioinformatics and Systems Biology, TheBurnham Institute, USAFrom Fold Recognition to Function Prediction

Professor Ian DawesUniversity of New South WalesRegulation 1-carbon metabolism in yeast; agentgenomic approach

Associate Professor Robert CaponSchool of Chemistry, University of MelbourneMolecular Bioprospecting: Is natural! Is good!

Dr Andrew PerkinsDepartment of Physiology. Monash University,MelbourneKruppel-like factors: three fingers in many pies

Professor Paul CareyDepartment of Biochemistry, Cleveland Centerfor Structural Biology, USARaman Crystallography

Dr Mark RizzacasaSchool of Chemistry, University of MelbourneTotal Synthesis of Biologically Active NaturalProducts

Professor Gottfried OttingKarolinska Institute, SwedenDipolar couplings, cross correlation andparamagnetism: a modern NMR toolbox.

Dr Bruce StillmanDirector, Cold Spring Harbour Laboratory, USAInheritance of chromosomes in eukaryotes

Dr Ben HankamerWolfson Laboratories (Centre for StructuralBiology) Biochemistry Department, ImperialCollege of Science, Technology and Medicine,London, UKStructure determination of photosynthetic andother macromolecular assemblies using singleparticle analysis, electron and X-raycrystallography.

Dr Vic ArcusSchool of Structural Biology, University ofAuckland, New ZealandStructural genomics and bacterial virulence:conservation and complexity in superantigengenes, architecture and activity.

Dr Brian GabrielliDepartment of Pathology, The University ofQueensland School of MedicineSpecific killing of tumour cells by drugs targetingcell cycle checkpoints.

Professor Art KriegDepartment of Internal Medicine and Departmentof Veterans Affairs Medical Center, University ofIowa and Coley Pharmaceutical Group, USAActions of Immunostimulatory DNA


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Professor Phillip RobinsonChildrens Medical Research Institute, SydneyProtein kinase regulation of synaptic vesicleendocytosis

Associate Professor Tracy BrownActing CEO and Executive Director of OperationsMeditech Research Ltd; Department ofBiochemistry and Molecular Biology, MonashUniversity, MelbourneThe clinical development of hyaluronic acidchemosensitising transport technology (hyacttm)in the treatment of cancer

Jeff DawsonDirector of Applications Development andSupport, Cray Inc, USABioinformatics and Supercomputer Technology -gene scanning and comparative genomics usingCray vector computer systems to provide extremeperformance

The IMB is committed tobuilding a culture of scientific

excellence, entrepreneurship andtechnological enterprise.

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The IMB’s Graduate Program grew substantiallythroughout its second year in 2001.

The 2000 inaugural class of IMB enrolled studentsgave presentations to their Thesis Committees aspart of the process to confirm their candidature.

New students had the opportunity to meet withThesis Committees, obtaining valuable input intotheir projects at an early stage.

The Graduate Education Committee, formed in2000, continued in its role to oversee the programand make recommendations to the IMB Executive.

The Graduate Coordinator, Ann Day, tookresponsibility for handling student matters and twostudent representatives provided ongoing dialoguebetween the student body and staff.

Graduate student enrolments increased during2001 with the IMB enrolling 28 PhD students andtwo MPhil students. A total of 12 Honoursstudents undertook their research projects withinthe IMB. Honours students enrol through thevarious schools of the University, enhancing theIMB’s collaborative relationships with theUniversity’s faculties.

In 2001 PhDs were awarded to five students:Sharon Clark, Iain Sharpe, Gos Schepers, YlvaStrandberg and David Wilson, and a Masters wasawarded to Nikolai Sokolenko.

IMB Graduate Program

IMB students shone brightly in 2001 with DavidPennisi and Michelle Hill both recommended onthe Dean’s list for outstanding theses. Julie Duttonwas awarded the Australian Society ofBiochemistry and Molecular Biology Fellowshipand an outstanding honours thesis was recognisedwhen IMB student Julia Pagan was awarded the2001 AMGEN Australia Prize for Molecular andCellular Biology.

The IMB’s Graduate Program ensures ourstudents receive a broad-based career training toequip them with the skills to tackle the scientificchallenges of the 21st century.

Graduate students participated in seminars andworkshops on the topics of intellectual property,patenting, venture capital, and ethics, legal andsocial issues of genetic technologies. A couple ofhighlights of the program included an informalbreakfast attended by Professor Wayne Hall fromthe IMB’s Office of Public Policy and Ethics, aswell as a Stem Cells Hypothetical, jointlypresented by the IMB and The Gene CRC andfeaturing Professor Bob Williamson.


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In August 2001, the IMB actively promoted theGraduate Program by taking part in theUniversity’s Postgraduate Study InformationEvening. Staff and students of the IMB talked toa range of individuals interested in undertakinggraduate studies across a diverse range of areas.

Visitors and exhibitors praised our display,commenting on the well-presented materials andenthusiasm of our staff and students alike.

The IMB is committed to graduate educationat the interface of biology, chemistry and computing.

SIMBA, the Students of the IMB Association,continued to effectively draw the students of theIMB together.

Throughout the year SIMBA organised a numberof social events that provided opportunities forstudents to discuss issues pertinent to their studiesand role within the IMB.

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Organisational Structure

Deputy Director(Systems & Administration)

Finance &Administration

LaboratoryServices

UNIVERSITY OF QUEENSLAND SENATE

Vice-Chancellor/IMB Board

Deputy Vice-Chancellor

Institute DirectorIMBcom BoardCEO IMBcomIMBcom Pty Ltd

IMB ScientificAdvisory Board

Office of PublicPolicy & Ethics

GraduateEducation Office

Marketing &Communications

Personnel &Human

Resources

InformationTechnology

Services

Bioinformatics &GenomicsDivision

Cellular &Developmental

Biology Division

Structural Biology& Chemistry

Division

Research Groups

The Institute

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Institute for Molecular Bioscience Board (as at 31 December 2001)

Professor John Hay Vice-Chancellor (Chair)

Professor Paul Greenfield Deputy Vice-Chancellor

Professor John Mattick AO Co-Director IMB

Professor Peter Andrews Co-Director IMB, CEO IMBcom

Professor Mick McManus Executive Dean (rotating)

Ms Helen Lynch AM Business Representative

Dr Russell Howard Biotechnology Industry Representative

Professor Frank Gannon International Scientist

Sir Sydney Schubert Community Representative

Mr Ross Rolfe State Government Representative

Mr Kevin Yearbury State Government Representative

Institute for Molecular Bioscience Scientific Advisory Board (as at 31 December 2001)

Professor John Mattick AO

Professor Peter Andrews

Professor Ken-ichi-Arai

Dr Mark Boguski

Professor Allan Bradley

Professor Wah Chiu

Professor Robert Graham

Professor John Hearn

Dr Leroy Hood

Professor Stephen Kent

Professor Edison Liu

Professor Garland Marshall

Professor Anne McLaren

Professor Ira Mellman

Professor Nicos Nicola

Professor Greg Petsko

Professor Robert Saint

Dr Douglas Williams

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Staff and students

DirectorsPeter Andrews, Co-director, IMBJohn Mattick, Co-director, IMBIan Taylor, Deputy Director, IMBWayneHall, Director, Office of Public Policy & Ethics

Group LeadersPaul AlewoodDavid CraikDavid FairlieSean GrimmondJennifer HallinanDavid HumeDavid JamesBostjan KobePeter KoopmanRichard LewisMelissa LittleJennifer MartinGeorge MuscatRobert PartonMark RaganJoseph RothnagelMark SmytheJennifer StowRick SturmRohan TeasdaleBrandon WainwrightMike WatersCarol WickingToshi YamadaAlpha Yap

IMB AssociatesSteve BarkerKevin BurrageMichael DentonIan FrazerJohn HancockMichael JamesDerek KennedyTom LoyAlisdair McDowallBryan MowryMatt Trau

Postdoctoral research officers –Senior Research OfficersJohn AbbenanteParamjit BansalGregory BourneJosephine BowlesNia BryantIan CassadyRoy HimesRichard KiddStephen LoveSally MartinAmanda NourseJane OlssonJoanne RedburnRobert ReidKatryn StaceyTrung Tran

Postdoctoral research officers –Research OfficerDenise AdamsTracy ArakakiNeil BoxJens BuchardtMonica BullejosAmanda CarozziPeter CassidyKallayanee ChawengsaksophakChristopher ClarkRichard ClarkSharon ClarkElaine CostelloeNathan CowiesonNorelle DalyUwe DresselTammy EllisLindsay FowlesAlison FranksMatthew GlennRoland GoversKarl HansfordMurray HargraveJonathan Harris

The Institute

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Begona HerasPaige Hilditch-MaguireJustine HillShu-Hong HuBixing (Ben) HuangLubomira JamriskaMarion LoughnanAndrew LuckeGemma MartinezFiona McMillanBrendan McMorranPierre-Francois MeryJuan Carlos Molero NavajasJorgen MouldAnnette NickeJulie OsborneJosef PanekRhonda PerrimanAlbert PolFiona RaePaavo RahkilaTimothy RavasiThomas RobertsonHorst SchirraJulie ScottPhilip SharpeGraeme ShepherdFiona SimpsonYogendra SinghAaron SmithYlva StrandbergMartin StoermerMatthew SweetJohan TryggParimala VajjhalaEllen vanDamCynthia WhitchurchJon WhiteheadDagmar WilhelmLorine WilkinsenMegan WilsonFiona WylieZheng Yuan

PhD StudentsSenali AbayratnaUdani AbeypalaChristelle AdolpheAzita AhadizadehChristopher ArmishawDaniel BarryScott BeatsonJennifer BoltonTom ChenAnthony CookLarry CroftMeredith DownesNicholas DrinnanJulie DuttonMelissa EdelingTimothy EvansJuliet FrenchBrooke GardinerSusan GilliesAndrew GoodallBrett HamiltonTamarind HamwoodGerald HartigGene HoppingDarryl HortonDouglas HortonWendy IngramKatherine IrvineAsanka KarunaratneMichael KelsoGabriel KolleMichael KorsinczkyCatherine LathamChristopher LeAndrew LeechDonmienne LeungJohn LockKelly LofflerFred MartinsonCarney MathesonKaren McCueEdwina McGlinnKevin MirandaIsabel Morrow

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Jason MulvennaDelvac OceandySusan NixonRyan O’DonnellJames PalmerLeonard PattendenMichael PiperJyotsna PippalManuel PlanTara RobertsPaul RohdeKarl RosengrenAngela SalimTedjo SasmonoRobert SbagliaGoslik SchepersKate SchroderIngrid SchroederDavid SesterIain SharpeRachael ShawAnnette ShewanShane SimonsenJames SmithNikolai SokolenkoStefan StanleyYlva StrandbergKhairina Tajul ArifinDimitra TemelcosManuela TrabiBudi UtamaNicole WalshShannon WalshMary WangJoyce WangStacey WardropChristine WellsCharlotte Widberg FlanaganDavid WilsonTakahiro Yasuda

Masters StudentsSaleh HasnawatiDarryl IrwinHelene JohansonChi-Yan Lau

Maria QuimioClaire WadeBo Wang

Honours StudentsJulia ArchboldJennifer BennettsPerpetina ChristyGillian GillmoreKelly Lammerts van BuerenAndrew McDevittNicholas MeadowsChristine MulfordJulia PaganAndrew PearsonNadya ShaleEmma SmithJoanna Starkey

Research AssistantsIan Bailey-MortimerJennifer BerkmanRenee BeyerTrudy BondSelena BoydDarren BrownVanessa CaigMarc CampitelliLucy CarterTara CartonStephen CronauJoanne DowdJacqueline EmeryCharles FergusonCameron FleggAlistair ForrestChristine GeeKylie GeorgasSimon GoldingBrett HoskingNing HuangDavid IrelandCarolyn JacobsKristy JamesRussell JarrottChris JohnsShannon Joseph

The Institute

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Markus KerrTatiana KhromykhAdrian KnightLynette KnowlesCaroline Ligny-LemaireRobert LuetterforstMadhavi MaddugodaLisa MarksAndrew McDevittRebecca McDonaldAllison McLeanAngela MorrisonTeresa MunchowJohn NormyleWarren OliverJulia PaganSarah PenningDarren PickeringAmanda PriorMichelle PullinEmily RileyKe-lin RuJennifer SargentDarren SmitNikolai SokolenkoDarrin TaylorElaine ThomasLinda ThomasLiam TownBrendan TseJuliana VenturatoSusie VermaDaying WenJacqueline WicksShayama WijedasaElizabeth WilliamsShaiyena WilliamsIan WilsonJason WyethGreg Young

Scientific SupportKarl ByrielAlun JonesDarren Paul

Adjunct appointmentsJudy HallidayTracie RamsdaleRobert RavenSangkot Marzuki

Visiting researchersTian-Huey LuGeorg RammDietmar Schomburg

Vacation and visiting scholars –Visiting ScholarSari AlataloUte MarxSally SlackJian SunJenny EkbergAngelica Figueroa Conde-ValvisEmma FornanderDaniel GottliebBert JanssenJenny PetterssonCarl Wibom

Vacation and visiting scholars –Vacation ScholarKim HanchardMichael HinesDaniel SangermaniOliver TamFraser Wright

Vacation and visiting scholars –UROP StudentSarah MaguireJessica MarDebby MelissenHeidi van Paassen

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Administration and FinanceTeresa Buckley, Executive SecretaryJodie Campbell, Reception/SecretaryBarbara Clyde, Administrative OfficerRobyn Craik, Reception/SecretaryAnn Day,

Personnel Manager & Graduate CoordinatorMileta Duggleby, Purchasing OfficerBarbara Feenstra, Reception/SecretaryAngela Gardner, Administrative OfficerCarole Key, Principal Administration OfficerKaren Korenromp, Finance ManagerRonda Turk, Reception/Finance AssistantSanta-Maria Trubshaw, Reception/Secretary

Technical and Laboratory ServicesRobyn Baird, Wash-up ManagerChristopher Barnett, Lab ManagerHendrick Faber, Technical AssistantGregory McHugh,

Technical Officer (Maintenance)Charles Nelson, Safety OfficerDavid Scarce, Workshop ManagerMichael Tetley, Glassware AttendantDawn Walsh, Glassware Attendant

Information Technology ServicesOndrej Hlinka, Computer Systems OfficerLuke Kirkwood, Computer Systems OfficerMaria Maddison, Computer Systems OfficerNelson Marques, Computer Systems OfficerLance Rathbone, Computer Systems OfficerPatrick Verhoeven, Computer Systems OfficerMing Ju (Calvin) Wang,

Computer Systems Officer

Marketing and CommunicationsRussell Griggs, Communications OfficerTania Hudspith, Marketing OfficerAngela Wallace, Education AssistantHelen Weatherley,

Marketing & Communications Manager

IMBcom Pty LtdPeter Andrews, CEO IMBcomDaniela Bellomo, Biotechnology AnalystAshley Bowen,

General Manager, Technology DevelopmentKellie Broderick, Executive AssistantLisa Edwards, Administration AssistantMichael Finney,

General Manager, Commercial DevelopmentKim Flanagan, Administrative AssistantDoug Horton, Commercial Intelligence AnalystWei-Lin (Maggie) Hsu,

Commercial Intelligence AnalystChristine Morrison, Business ManagerKathryn Nielsen, Manager,

Intellectual Property & Business AnalysisPeter Riddles,

General Manager, Corporate DevelopmentAlan Scott, Finance ManagerDavid Wilson, Commercial Intelligence Analyst

The Institute

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98

Financial statement of operating income and expenditureYear ended 31 December 2001

INCOME:2000 2001

Note ($AUD) ($AUD)University of Queensland (Operating Grant) 1 2,942,718 6,664,365University of Queensland Research Grants 200,990 100,000State Government 2 5,500,000 2,500,000SRC Grant (Australian Research Council) 1,631,153 1,039,320Australian Research Council 3 1,131,271 1,668,000Clive and Vera Ramaciotti Foundation 43,545 9,545CRC for Discovery of Genes for Common Human Diseases 220,958 232,415Diabetes Australia Research Trust 33,409 35,791Department of Industry Science and Technology 166,400 0Human Frontiers Science Program 127,242 0Glaxo Welcome Australia 670,000 62,000Government Employees Medical Research Fund 45,000 0Juvenile Diabetes Foundation International 299,626 267,704Mayne Bequest Foundation 60,000 0The Merck Genome Research Institute 261,559 0National Health and Medical Research Council 3 2,938,586 5,359,112National Heart Foundation 45,000 0Post Graduate Scholarships 28,209 15,882Queensland Cancer Fund 230,072 116,447Sylvia and Charles Viertel Charitable Foundation 165,000 165,000Wellcome Trust 28,011 23,829Commercial Income 1,371,664 2,589,861Miscellaneous Income 415,591 272,136

TOTAL INCOME: $18,556,004 $21,121,405

Funds brought forward from previous year 4 $1,009,031 $3,843,597

TOTAL FUNDS AVAILABLE $19,565,034 $24,965,002

EXPENDITURE:

Salaries-Research 6,549,841 7,809,255 -Administration 1,090,220 1,117,375 -Infrastructure 541,043 813,527Research Services 2,635,745 6,034,723Education Programs 5 317,726 378,436Administration 6 937,703 550,574Infrastructure 7 357,436 928,651Capital Equipment 8 2,307,116 3,132,769IMBcom 984,608 605,214

TOTAL EXPENDITURE: $15,721,437 $21,370,523

Funds carried forward: 9 $3,843,597 $3,594,479

Financials

99

1/ In-kind ContributionsFigure does not include the following salaries for jointappointments paid by other departments:

Department %

S. Barker Parasitology 80

D. Hume Biochemistry 20

T. Loy Anthropology & Sociology 100

J.Mattick Biochemistry 20

R.Parton Micoscopy & Microanalysis 10

J.Rothnagel Biochemistry 80

B.Wainwright Biochemistry 20

M.Waters Physiology & Pharmacology 100

A.Yap Physiology & Pharmacology 80

B.Kobe Biochemistry 80

2/ State Government Funding received inadvance for 2001

1,750,000

3/ Fellowship/Projects from Government AgenciesAustralian Research CouncilProjects 1,316,608Fellowships 351,392

1,668,000National Health and Medical Research CouncilProjects 4,450,336Fellowships 908,776

5,359,112

4/ Funds brought Forward from 2000University of Queensland Operating Grant 71,883University of Queensland Research Grants 66,234Post Graduate Scholarships 4,937State Government 1,961,398SRC Grant 513,119Fellowships (as approved by funding bodies) 15,685Project Grants (as approved by funding bodies) 1,210,339

3,843,597

5/ Education ProgramsPostgraduate scholarships 332,299Postgraduate recruitment & training 30,180Public Policy & Ethics 15,958Total Education Services 378,436

Explanatory notes to statement of income and expenditure

6/ AdministrationAnnual Report 29,426Marketing 18,446Personnel Recruitment and Training 70,715Visiting Scientists/Seminars 22,207Fees 252,311Entertaining 25,730Equip Lease 22,249Photocoping 13,436Postage and Freight 12,023Printing and Stationery 63,260Telephone 48,686Travel Expenses 16,887Sundries 14,465Cost Recovery -59,268Total Administration 550,574

7/ InfrastructureBuilding Maintenance 71,373Rental - Demountables/Storage 29,722Renovations 234,696Laundry 1,931Minor Equipment & Furniture 35,246Equipment Maintenance 211,253Animals 83,890Computer Services 119,420Glass washing and replacement 17,617Reticulated gases, RO water & dry ice 58,511Sundries 27,349Stores 37,642Total Infrastructure 928,651

8/ Capital EquipmentScientific Equipment 2,606,495Minor Equipment 526,275Total Capital Equipment 3,132,769

9/ Funds carried forward to 2002University of Queensland Operating Grant 1,619,317University of Queensland Research Grants -232Post Graduate Scholarships 3,544State Government -150,411SRC Grant 164,880Fellowships (as approved by funding bodies) 77,703Project Grants (as approved by funding bodies) 1,879,678

3,594,479

100

How can we help you?

Institute for Molecular BioscienceThe University of Queensland, St Lucia Qld 4072

Ph: (07) 3365 1271 Fax: (07) 3365 4388Email: [email protected]

Website: www.imb.uq.edu.au

The IMB is committed to building partnerships and collaborations with industry, government and otherresearch organisations, contributing to world knowledge in terms of human and animal biology as well ashealth benefits for the global community, and ethics of the new genetics. In particular, the IMB is developing:

• partnerships with hospitals and medical research institutes to provide a better understanding of thegenetic and biochemical basis of disease, and to develop and trial clinical candidates emerging fromits research programs.

• strategic alliances with national and international pharmaceuticals to build technology platformsand develop novel pharmaceuticals based on the Institute’s research programs.

• collaborations with mathematicians and computational scientists to develop new programs inbioinformatics and biological information theory which will have an impact on future design ofcomputers and information systems.

• joint ventures with the CSIRO and Queensland Department of Primary Industries to transfer IMB’stechnologies and utilise its facilities for the development of products for plant and livestock industries.

• exchange programs with national and international educational institutions to build a diversity ofskills across cultures and disciplines, and to enhance the IMB’s ability to contribute to the developingworld.

To explore how the IMB can build its relationship with your organisation or research group, please callthe IMB today or alternatively, please complete and return this page.

Please arrange for a representative of the Institute for Molecular Bioscience to call me to discusspotential collaborations.

Please send me more information about supporting the work of the Institute.

Please send me the Institute’s Scientific Annual Report and newsletter.

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This report was designed, edited and produced byDavid Fairlie, Teresa Buckley and the IMB Marketing Team

Institute for Molecular Biosciencewww.imb.uq.edu.au

Institute for Molecular B

ioscience 2001 Annual R

eport

Documents

Institute for Molecular Bioscience Annual Report 2001 · Contribute to world knowledge - human and animal biology, health and medicine Create a platform for excellence in fundamental